Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2019 Apr 1;176(14):2343–2357. doi: 10.1111/bph.14617

Updates in the function and regulation of α1‐adrenoceptors

Juliana Akinaga 1, J Adolfo García‐Sáinz 2, André S Pupo 1,✉
PMCID: PMC6592863  PMID: 30740663

Abstract

α1‐Adrenoceptors are seven transmembrane domain GPCRs involved in numerous physiological functions controlled by the endogenous catecholamines, noradrenaline and adrenaline, and targeted by drugs useful in therapeutics. Three separate genes, whose products are named α1A‐, α1B‐, and α1D‐ adrenoceptors, encode these receptors. Although the existence of multiple α1‐adrenoceptors has been acknowledged for almost 25 years, the specific functions regulated by each subtype are still largely unknown. Despite the limited comprehension, the identification of a single class of subtype‐selective ligands for the α1A‐ adrenoceptors, the so‐called α‐blockers for prostate dysfunction, has led to major improvement in therapeutics, demonstrating the need for continued efforts in the field. This review article surveys the tissue distribution of the three α1‐adrenoceptor subtypes in the cardiovascular system, genitourinary system, and CNS, highlighting the functions already identified as mediated by the predominant activation of specific subtypes. In addition, this review covers the recent advances in the understanding of the molecular mechanisms involved in the regulation of each of the α1‐adrenoceptor subtypes by phosphorylation and interaction with proteins involved in their desensitization and internalization.

Linked Articles

This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Abbreviations

BPH

benign prostatic hyperplasia

GRK

GPCR kinase

1. INTRODUCTION

The actions of adrenaline and noradrenaline result from the activation of nine different adrenoceptors. All nine adrenoceptors belong to the superfamily of GPCRs, the most numerous family of membrane proteins (Fredriksson, Lagerstrom, Lundin, & Schioth, 2003; Fredriksson & Schioth, 2005). Adrenoceptors are classified into three subfamilies, α1‐, α2‐, and β‐ adrenoceptors, based on their pharmacological profiles, major coupling to signalling pathways (Hieble et al., 1995) and phylogeny. Using the latter criteria, adrenoceptors belong to the amine receptor cluster of the rhodopsin family (Fredriksson & Schioth, 2005) or to subfamily A, group 17 (Joost & Methner, 2002). For the accepted nomenclature, classification, databases, and other tools, see the following: IUPHAR/BPS guide for pharmacology (Harding et al., 2018; Sharman et al., 2018; and http://www.guidetopharmacology.org).

This review deals with advances in the function and regulation of each of the α1‐adrenoceptor subtypes; for additional aspects, readers are directed mainly to the reviews mentioned in this text, the references therein, and to Alexander et al. (2017).

2. INTRACELLULAR SIGNALLING BY α1‐ADRENOCEPTOR SUBTYPES

The classical intracellular signalling pathway triggered by all three α1‐adrenoceptor subtypes results from coupling to Gq/11 proteins, leading to the activation of phospholipase Cβ, hydrolysis of phosphatidylinositol 4,5‐bisphosphate into DAG/inositol trisphosphate, intracellular calcium mobilization, and PKC activation (Figure 1a; Hieble et al., 1995). Upon receptor activation, GPCR kinases (GRKs) and/or PKC phosphorylate α1‐adrenoceptors, leading to the recruitment of β‐arrestins. Moreover, β‐arrestins act as a scaffolding for other proteins triggering a distinct array of G‐protein independent signalling through the activation of ERK1/2 (Figure 1b; Perez‐Aso et al., 2013; Segura et al., 2013).

Figure 1.

Figure 1

Open in a new tab

(a) Schematic representation of the classical Gq protein dependent signalling triggered by α1‐adrenoceptor subtypes and (b) of the signalling triggered by receptor phosphorylation and interaction with β‐arrestin, which is also involved in receptor internalization. IP3: inositol trisphosphate; PIP2: phosphatidylinositol 4,5‐bisphosphate; PLC: phospholipase Cβ

It is worth mentioning that constitutive activity has been observed for native α1D‐ adrenoceptors in rat arteries (Gisbert et al., 2002; Gisbert, Noguera, Ivorra, & D'Ocon, 2000; Noguera, Ivorra, & D'Ocon, 1996; Ziani, Gisbert, Noguera, Ivorra, & D'Ocon, 2002) and in cells overexpressing recombinant α1D‐ adrenoceptors (García‐Sáinz & Torres‐Padilla, 1999; Rodríguez‐Pérez, Romero‐Ávila, Reyes‐Cruz, & García‐Sáinz, 2009); meanwhile, weak inverse agonism has been observed in some cells expressing native α1A‐ or α1B‐ adrenoceptors (Cotecchia, 2007). However, using site‐directed mutagenesis, constitutively active mutants have been generated and inverse agonism has been detected (Cotecchia, 2007). Many of the currently used α1‐adrenoceptor antagonists are, in fact, inverse agonists (Cotecchia, 2007; García‐Sáinz & Torres‐Padilla, 1999; Rodríguez‐Pérez et al., 2009).

3. α1‐ADRENOCEPTORS IN PHYSIOLOGY AND PHYSIOPATHOLOGY

The α1‐adrenoceptor subfamily is composed of three members, that is, α1A‐, α1B‐, and α1D‐ adrenoceptors (Hieble et al., 1995). These receptors participate in a large number of physiological processes and in the pathogenesis of diseases (for reviews, see García‐Sáinz, Vázquez‐Prado, & Medina, 2000; Garcia‐Sainz, Vazquez‐Prado, & Villalobos‐Molina, 1999; Michelotti, Price, & Schwinn, 2000; Tanoue et al., 2003; Toews, Prinster, & Schulte, 2003). The latter has been regarded as the “dark side” of these transducers' actions, but, in our opinion, a better understanding of the molecular pharmacology of these receptors might lead to a path of light and hope, offering opportunities for novel therapeutic interventions. The sections below survey the roles of α1‐adrenoceptor subtypes in the cardiovascular system, genitourinary system, and CNS with regard to health and disease. Figure 2 summarizes some of the important functions controlled by α1‐adrenoceptor subtypes in these systems.

Figure 2.

Figure 2

Open in a new tab

Summary of the main functions identified for each of the α1‐adrenoceptors subtypes in the cardiovascular system, genitourinary system, and CNS. Readers are referred to the text for the bibliography

3.1. α1‐Adrenoceptors in arteries

Among the best characterized α1‐adrenoceptor‐mediated actions are those in the vascular system, where they are distributed across adventitial, medial smooth muscle, and endothelial cells (see McGrath, 2015). However, information on the role of each of the individual α1‐adrenoceptor subtype is limited to receptors expressed in vascular smooth muscle. Exceptions are the clear identification of NO production in endothelial cells from the rat aorta by α1A‐ adrenoceptors (Arce et al., 2017), by α1B‐adrenoceptors in cultured endothelial cells from coronary arteries (Jensen, Swigart, Montgomery, & Simpson, 2010), and by α1D‐ adrenoceptors in endothelial cells from the rat mesenteric vascular bed and carotid artery (de Andrade et al., 2006; Filippi et al., 2001). With the increasing recognition of the importance of the perivascular adipose tissue for normal vascular function (Bulloch & Daly, 2014), it is expected that the roles of individual α1‐adrenoceptor subtypes in the tunica adventitia will be soon elucidated.

Although the vascular system expresses all three α1‐adrenoceptors, there is a predominance of specific subtypes in different arteries. An interesting view emerged in which the prevalence of an α1‐adrenoceptor subtype in a vessel depends on the density of sympathetic innervation and on the vessel calibre (Stassen, Maas, Schiffers, Janssen, & De Mey, 1998). The α1A‐ adrenoceptors predominate in resistance arteries such as the small mesenteric artery (Marti et al., 2005; Methven, McBride, Wallace, & McGrath, 2009; Nourian et al., 2008; Philipp & Hein, 2004) and distributing arteries such as the renal (Hrometz et al., 1999) and tail (Kamikihara et al., 2005; Lachnit, Tran, Clarke, & Ford, 1997; Taki et al., 2004) arteries. Conversely, α1D‐ adrenoceptors are more prevalent on less innervated conductance arteries including the aorta, femoral, iliac, carotid, pulmonary, and superior mesenteric arteries (Arevalo‐Leon, Gallardo‐Ortiz, Urquiza‐Marin, & Villalobos‐Molina, 2003; Gisbert et al., 2000; Hussain & Marshall, 1997; Marti et al., 2005; Methven, Simpson, & McGrath, 2009; Nourian et al., 2008; Piascik et al., 1995; Rudner et al., 1999). This differential distribution of α1A‐adrenoceptors indicates physiological relevance; the dominant α1D‐ adrenoceptors in conductance arteries result in high sensitivity to catecholamines, and the activation of this subtype leads to persistent vasoconstriction that tends to continue even after agonist removal, preventing sudden changes in the vessel calibre during variations in the circulating levels of catecholamines (Flacco et al., 2013; Gisbert et al., 2000; Noguera et al., 1996; Ziani et al., 2002). On the other hand, in the more densely innervated smaller resistance arteries, noradrenaline released from sympathetic terminals activates α1A‐ adrenoceptors and causes less sustained vasoconstriction allowing rapid vascular tonus adjustment in response to autonomic activation. The positive relationship between the density of adrenergic fibres and dominance of α1A‐ adrenoceptors is reversible, as sympathetic denervation increases the expression and participation of the other two subtypes in vasoconstriction (Kamikihara et al., 2005; Kamikihara et al., 2007; Stassen et al., 1998; Taki et al., 2004). In addition, the potencies of antipsychotics in producing orthostatic hypotension correlated with their affinities for α1A‐ adrenoceptors but not for α1D‐ adrenoceptors (Nourian et al., 2008), as most of the antipsychotics behave as competitive antagonists of α1‐adrenoceptors, and this positive correlation further indicates that noradrenaline released from sympathetic terminals targets the α1A‐ adrenoceptors to increase peripheral vascular resistance.

Whereas the roles of the α1A‐ and α1D‐ adrenoceptors in vasoconstriction were promptly recognized, evidence for the participation of α1B‐adrenoceptors is scarce. The lack of subtype‐selective α1B‐adrenoceptor ligands limits the understanding of the role of this subtype in the vascular system. Nevertheless, studies in α1B‐adrenoceptor knockout mice indicate that this subtype plays a minor role in vascular homeostasis, acting mainly as a modulator of the other two receptors' activities (Cavalli et al., 1997; Cotecchia, 2010; Daly et al., 2002; Docherty, 2010; Tanoue et al., 2003).

In several animal models, hypertension has been associated with increased α1D‐ adrenoceptor signalling (Gisbert et al., 2002; Ibarra, Terrón, López‐Guerrero, & Villalobos‐Molina, 1997; Villalobos‐Molina et al., 2008; Villalobos‐Molina & Ibarra, 1999; Villalobos‐Molina & Ibarra, 2005; Villalobos‐Molina, López‐Guerrero, & Ibarra, 1999). Activation of α1D‐adrenoceptors increases protein synthesis and vascular wall growth (Erami, Zhang, Ho, French, & Faber, 2002; Xin, Yang, Eckhart, & Faber, 1997). In an angiotensin II‐induced hypertension and aortic hypertrophy model, α1D‐ adrenoceptor antagonists do not prevent hypertension, but do inhibit vascular hypertrophy, dissociating both events and suggesting a role for α1D‐ adrenoceptors in the long‐term vascular hypertrophic process (Gallardo‐Ortiz et al., 2015).

The roles of catecholamines and α1‐adrenoceptors in pulmonary hypertension induced by chronic exposure to reduced oxygen was examined in wild‐type (WT) and knockout mice. The decreased luminal area and increased wall thickness of the arteries induced by hypoxic conditions in WT mice were markedly reduced in dopamine β‐hydroxylase knockouts as well as in α1A‐ or α1B‐adrenoceptor‐deficient mice, strongly suggesting that the activation of these receptors by noradrenaline/adrenaline contributes to the vascular remodelling in hypoxic pulmonary hypertension (Faber et al., 2007).

Although α1‐adrenoceptor antagonists are antihypertensive, orthostatic hypotension and the worsening of heart failure, along with the availability of better alternatives, have considerably decreased their prescription. Currently, the α1‐adrenoceptors in the vascular system are targets for agonists to promote vasoconstriction. Thus, α1‐adrenoceptor agonists such as phenylephrine, are components of oral over‐the‐counter medications to alleviate the congestive symptoms of the common cold and influenza. In addition, the imidazolines, oxymetazoline and naphazoline, are common components of topical nasal decongestants, mydriatic eye drops, and more recently dermatological formulations for the treatment of facial erythema in rosacea (Kircik et al., 2018; Mota & Norris, 2016; Vaidyanathan, Williamson, Clearie, Khan, & Lipworth, 2010). Interestingly, oxymetazoline and naphazoline are low efficacy agonists with reasonable selectivity for α1A‐ adrenoceptors (10‐ to 30‐fold; Akinaga et al., 2013; Minneman, Theroux, Hollinger, Han, & Esbenshade, 1994), further supporting the relevance of this subtype in vasoconstriction. However, the prolonged use of these topical agonists is limited by tachyphylaxis leading to rebound congestion and hyperaemia, opening the possibility for the development of better agonists that are less tachyphylactic than those currently available.

Intravenous α1‐adrenoceptor agonists are indispensable medications in emergency and intensive care units to raise BP in shock (Colling, Banton, & Beilman, 2018; Jentzer et al., 2018). The most used α1‐adrenoceptor agonists to revert hypotension are noradrenaline, adrenaline, dopamine, and phenylephrine. Recently, a shortage in the noradrenaline supply to US hospitals was associated with increased mortality among patients with septic shock (Vail et al., 2017). In septic shock, reversal of hypotension with the currently available vasoconstrictors is limited by tachyphylaxis because vasoconstriction diminishes as treatment continues, resulting in inadequate blood perfusion and vital organ failure. It has been proposed that the loss of vasoconstriction due to α1‐adrenoceptor agonists in septic patients might result from receptor desensitization (Geloen et al., 2015; Hwang, Lau, Huang, Chen, & Liu, 1994), and again, the development of ligands that are less tachyphylactic than the natural catecholamines and phenylephrine would be a significant improvement in the emergency treatment of hypotension by providing more sustained elevation of BP.

3.2. α1‐ Adrenoceptors in the heart

α1‐ Adrenoceptors participate in the development, growth, and function of the heart. Current evidence indicates that the α1A‐ and α1B‐adrenoceptors are present in the myocardium, modulating contractility, whereas the α1D subtype is found in coronary arteries, regulating heart perfusion (O'Connell, Jensen, Baker, & Simpson, 2014). It has been recently proposed that all ventricular myocytes in the mouse heart express the α1B‐adrenoceptors (and β1‐adrenoceptors), whereas the α1A‐ adrenoceptors are present in half of these cells and co‐expressed with α1B‐adrenoceptors (Myagmar et al., 2017). These receptors also play an important role in cardiac hypertrophy (reviewed in Cotecchia, Del Vescovo, Colella, Caso, & Diviani, 2015; O'Connell et al., 2014; Woodcock, Du, Reichelt, & Graham, 2008). Cardiac hypertrophy is characterized by an abnormally large myocardial mass that reflects, among other changes, an increased cardiomyocyte size and is often accompanied by heart failure. The development of α1‐adrenoceptor‐mediated cardiomyocyte hypertrophy depends on classical signalling through Gq proteins and, probably, through β‐arrestins, leading to the activation of MAPKs, modulation of transcription factors, and ultimately to hypertrophy (Cotecchia et al., 2015; O'Connell et al., 2014; Woodcock et al., 2008). Interestingly, in addition to this canonical signalling pathway, there is evidence indicating that α1‐adrenoceptors are also present in cardiomyocyte nuclei, from where they signal likely through Gq, phospholipase Cβ, inositol trisphosphate, and calcium to induce hypertrophy (Dahl et al., 2018; O'Connell et al., 2014; Wu & O'Connell, 2015). This is an interesting new paradigm that might have important physiological and pharmacological implications, including ligand transport into the cells, ligand lipophilicity, and the possible roles of transporters (O'Connell et al., 2014).

Surprisingly, the activation of α1‐adrenoceptors appears to be beneficial for some cardiac conditions. This sounds counterintuitive and, in fact, runs contrary to some relatively recent medical ideas. Agonists of α1‐adrenoceptors ameliorate ischaemia reperfusion injury, chemotherapy‐induced cardiotoxicity, and calcium overload, among other noxious events or drugs (reviewed in Jensen, O'Connell, & Simpson, 2011; Perez & Doze, 2011). Similarly, experimental and clinical trial data have suggested that α1‐adrenoceptor antagonists might worsen some cases of heart failure (Jensen et al., 2011). It has been suggested that α1‐adrenoceptor agonists could provide cardio‐protection (Jensen et al., 2011; Perez & Doze, 2011), particularly those selective for the α1A subtype (Cowley et al., 2017). Consistent with this, in transgenic mice adrenergic‐induced ischaemic‐preconditioning is mediated by α1A‐ adrenoceptors (Perez & Doze, 2011).

3.3. α1‐Adrenoceptors in the genitourinary system: Ureter, urinary bladder, urethra, and prostate

Benign prostatic hyperplasia (BPH), an enlarged prostate frequently accompanied by lower urinary tract symptoms, such as acute urine retention, is very common in men 40 years old and older. The prostate expresses α1‐adrenoceptors, predominantly the α1A subtype (Price et al., 1993; Faure, Pimoule, Vallancien, Langer, & Graham, 1994) and this subtype mediates prostate contraction (Forray et al., 1994), and the enlarged prostate compresses the urethra leading to difficulties in micturition. Tamsulosin, the first α1A‐ adrenoceptor selective drug used to alleviate the symptoms of BPH, was a major step in improving the pharmacological treatment of patients. This and related drugs are recommended as first‐line treatments for patients with BPH by medical associations (McVary et al., 2011; Oelke et al., 2013). Although most of the patients have a good clinical response, others require additional treatments. Among those are the use of 5‐α‐reductase inhibitors and antagonists of other receptors, which could be involved in the pathogenesis of the disease and its symptoms, such as α1D‐ adrenoceptors and 5‐HT receptors (McVary et al., 2011; Oelke et al., 2013). The development of drugs with selectivity for several of these receptors is in progress (see Chagas‐Silva et al., 2014; Nascimento‐Viana et al., 2016).

All three α1‐adrenoceptors are present in the human ureter, albeit the α1A‐ and α1D‐ adrenoceptors seem to be more abundant than the α1B‐subtype (Sigala et al., 2005). This forms the basis for one of the several off‐label uses of prazosin and other α1‐adrenoceptor antagonists in facilitating stone expulsion in urolithiasis through the relaxation of the ureter smooth muscle.

α1‐ Adrenoceptors are expressed in both the bladder and urethra from different species and are described to be involved in dysfunctions of these organs (Alexandre et al., 2017; Michel & Vrydag, 2006). Phenylephrine contracts the bladder neck, indicating that the control of the tonus of this region involves activation of α1‐adrenoceptors (Michel & Vrydag, 2006). A recent study showed that male and female proximal urethra from mice and marmoset present striking differences in the presence of α1‐adrenoceptor subtypes, indicating that urinary retention might involve different mechanisms depending on gender (Alexandre et al., 2017). Although α1A‐ adrenoceptors seem to be the main functional subtype in both genders, the contractions in response to phenylephrine are more vigorous in male, compared with those in female, urethra.

3.4. α1‐Adrenoceptors in the genitourinary system: Epididymis, vas deferens, and seminal vesicle

From a biological and evolutionary perspective, α1‐adrenoceptors in the reproductive system are essential for male fertility and therefore for the existence of a species. Knocking out both α1A‐ adrenoceptors and P2X1 purinoceptors in male mice leads to complete infertility (White et al., 2013). During the emission phase of ejaculation, sympathetically released noradrenaline and ATP produce forceful contractions of the epididymis, vas deferens, seminal vesicles, urethra, and prostate, propelling the semen towards the urethral meatus. The complete infertility of the α1A‐ P2X1 knockout mice results from the lack of contractility of these organs, as sperm collected from the epididymis still fertilizes ova in vitro. The key role for α1A‐ adrenoceptors in reproduction is also demonstrated by the fact that the knockout of either α1B‐ or α1D‐adrenoceptors has no effect on male fertility (Cavalli et al., 1997; Sanbe et al., 2007; Tanoue, Koshimizu, & Tsujimoto, 2002). On the other hand, knocking out only the α1A‐ adrenoceptors reduces the fertility rate by 50%, whereas the triple α1‐adrenoceptor knockout male mice are infertile (Sanbe et al., 2007).

Transcripts encoding all three α1‐adrenoceptors have been found in organs of the male reproductive tract from rodents and humans, albeit in different proportions with relatively similar levels for α1A‐ and α1D‐ but lower levels for α1B‐adrenoceptors (Avellar, Lazari, & Porto, 2009; Burt, Chapple, & Marshall, 1995; Mendes, Hamamura, Queiroz, Porto, & Avellar, 2004; Pacini, Castilho, Hebeler‐Barbosa, Pupo, & Kiguti, 2018; Pupo, 1998; Queiroz, Mendes, Porto, & Avellar, 2002; Silva, Megale, Avellar, & Porto, 1999; Yono et al., 2012). However, in isolated tissue preparations, the contractions of these organs in response to α1‐adrenoceptor agonists are often described as mediated by the α1A‐subtype (Avellar et al., 2009; Burt et al., 1995; Mendes et al., 2004; Pacini et al., 2018; Pupo, 1998; Silva et al., 1999; Yono et al., 2012). Importantly, the contractions of the mouse and rat vas deferens in response to electrical field stimulation have been described to involve α1D‐ adrenoceptors, and at least in the mouse vas deferens, these receptors seem to play a role in contractions to exogenous noradrenaline (Bexis et al., 2008; Cleary, Slattery, Bexis, & Docherty, 2004; Mallard, Marshall, Sithers, & Spriggs, 1992). Therefore, it has been proposed that the α1A‐ and α1D‐ adrenoceptors are differentially located in relation to the sympathetic neuro‐effector junction in the vas deferens, where the latter is more readily accessed by noradrenaline released from sympathetic nerve terminals than the former (Docherty, 2010).

3.5. α1‐ Adrenoceptors in the CNS

α1‐ Adrenoceptors are the most abundant adrenoceptors in the CNS. However, knowledge on their localization and function has been hampered by the lack of subtype‐selective antibodies, selective ligands with good brain barrier permeability, and the intrinsic complexity of brain functions. Despite these difficulties, significant knowledge has been gained with the use of genetically engineered mice (Koshimizu, Tanoue, & Tsujimoto, 2007; Perez & Doze, 2011; Tanoue et al., 2002, 2003; Zuscik et al., 2000). Studies with α1B‐adrenoceptor knockout mice showed the involvement of this subtype in memory consolidation and fear‐motivated exploratory activity (Tanoue et al., 2002, 2003), whereas the overexpression of these receptors results in marked apoptotic neurodegeneration accompanied by locomotor impairment and seizures (Zuscik et al., 2000). Interestingly, the behavioural activation produced by modafinil, one of the most prescribed drugs for attention‐deficit disorder and hyperactivity syndrome, is markedly attenuated in α1B‐adrenoceptor knockout mice, whereas in WT mice, this effect is blocked by terazosin (a non‐selective α1‐adrenoceptor antagonist) but not by WB‐4101 (selective α1A‐/α1D‐ adrenoceptor antagonist) or BMY‐7378 (selective α1D‐ adrenoceptor antagonist; Stone, Cotecchia, Lin, & Quartermain, 2002). These findings implicate the α1B‐adrenoceptors in the mechanism of action of modafinil. Changes in the seizure thresholds to chemoconvulsants have also been observed in mice expressing constitutively active α1A‐ or α1B‐adrenoceptors (Perez & Doze, 2011). Alterations in cognitive functions have also been detected in α1A‐ adrenoceptor knockout mice, whereas chronic stimulation of α1A‐ adrenoceptors increases neurogenesis, enhances learning and memory, and improves the mood (reviewed in Perez & Doze, 2011). It has been suggested that the brain α1‐adrenergic system could be altered in depression (Stone, Lin, Rosengarten, Kramer, & Quartermain, 2003) and post‐traumatic stress disorder (Roepke et al., 2017).

4. REGULATION OF α1‐ADRENOCEPTORS BY PHOSPHORYLATION

Protein phosphorylation is among the major regulators of cell function. Initially discovered as a process that modulates glycogen metabolism, it later became clear that protein phosphorylation/dephosphorylation cycles regulate essentially all major life processes in cells, including overall metabolism, cell cycle, secretion and motility (see historical perspective in Cohen, 2002).

The α1‐adrenoceptors are phosphorylated, and this is a key regulatory process for these receptors (Cotecchia et al., 2004; Cotecchia, Scheer, Diviani, Fanelli, & De Benedetti, 1998; García‐Sáinz et al., 2000; Vázquez‐Prado, Casas‐González, & García‐Sáinz, 2003). The activation of PKC in rat hepatocytes blocked or desensitized α1‐adrenoceptor activity, suggesting that the receptor activity could be regulated by phosphorylation (Corvera & García‐Sáinz, 1984). Receptor phosphorylation was later experimentally shown using DDT1‐MF‐2 cells, a hamster smooth muscle cell line (Leeb‐Lundberg et al., 1985) that, like the rat hepatocytes, expresses the α1B subtype. It is now known that α1B‐adrenoceptors are phosphorylated in response to α1‐adrenoceptor agonists and to a large variety of other agonists that act through different receptors, including GPCRs, receptor tyrosine kinases, receptors with serine/threonine kinase activity (TGF‐β), and intracellular receptors (see Cotecchia et al., 1998; Cotecchia et al., 2004; García‐Sáinz et al., 2000; García‐Sáinz, Romero‐Ávila, & Alcántara‐Hernández, 2011; Vázquez‐Prado et al., 2003). Evidence that the other α1‐adrenoceptors are also phosphorylated was subsequently reported (García‐Sáinz, Rodríguez‐Pérez, & Romero‐Ávila, 2004; García‐Sáinz, Vázquez‐Cuevas, & Romero‐Ávila, 2001; Vazquez‐Prado, Medina, Romero‐Avila, Gonzalez‐Espinosa, & Garcia‐Sainz, 2000).

Figure 3 illustrates the substrates for phosphorylation (serine/threonine residues; large red, yellow, and blue circles) in the intracellular domains of the three human α1‐adrenoceptor subtypes identified by mutagenesis and functional analysis (Diviani et al., 1996; Lattion, Diviani, & Cotecchia, 1994) or through MS and functional work (Alcantara‐Hernandez et al., 2017; Alfonzo‐Méndez, Carmona‐Rosas, Hernández‐Espinosa, Romero‐Ávila, & García‐Sáinz, 2018; Carmona‐Rosas, Hernández‐Espinosa, Alcántara‐Hernández, Alfonzo‐Méndez, & García‐Sáinz, 2018).

Figure 3.

Figure 3

Open in a new tab

Schematic representation of the substrates for phosphorylation currently identified in the three human α1‐adrenoceptors (AR) subtypes (large red, yellow, and blue circles). Phosphorylated residues in the α1A‐ and α1D‐ adrenoceptors were identified by MS (Alcantara‐Hernandez et al., 2017; Alfonzo‐Méndez et al., 2018), whereas for the α1B‐adrenoceptor, the residues were identified by site‐directed mutagenesis and functional analysis of the hamster orthologue (Diviani et al., 1997; in parenthesis are the sites defined for the hamster receptor). Below the diagram are the sequence alignments of the third intracellular loop and the carboxyl terminus (C‐tail) of the three human α1‐adrenoceptor subtypes. Phosphorylated amino acids are marked in colour. Symbols: (a) “*” indicates single fully conserved residue; (b) “:” indicates conservative among subtypes; and (c) “.” non‐conservative among subtypes

The pioneer work of Diviani, Lattion, and Cotecchia (1997) and Lattion et al. (1994) showed that the key phosphorylation sites of the α1B‐adrenoceptor activated by adrenaline were located in the intracellular C‐tail and correspond to five serines: three of them are substrates for GRKs and the remaining two for PKC (Figure 3). However, truncation of the C‐tail of the α1A‐ (Price, Morris, Biswas, Smith, & Schwinn, 2002) and α1D‐ adrenoceptor (Rodríguez‐Pérez et al., 2009) rendered receptors that could be phosphorylated in response to agonists and PKC activation by phorbol esters, indicating the existence of phosphorylation sites in addition to those in the C‐tail of these subtypes.

Considerable evidence indicates that the bulk and charge changes induced by receptor phosphorylation are not enough to explain the outcomes in signalling and cellular location. Therefore, it was hypothesized that the phosphorylation of specific residues results in a “barcode” pattern that in turn determines a receptor's fate (reviewed in Tobin, 2008; Tobin, Butcher, & Kong, 2008; see also Butcher et al., 2011). It has been proposed that the residues that are phosphorylated in a given receptor may change according to the cell type in which it is expressed, the type of stimulus to which such cells are subjected, and most importantly, the long‐term response observed (Tobin, 2008; Tobin et al., 2008). This has markedly increased the interest in defining the phosphorylated sites and their functional importance. Considerable effort has been made during recent years to define this for a variety of receptors, mainly using partial affinity purification and MS (see some recent examples: Alfonzo‐Méndez, Alcántara‐Hernández, & García‐Sáinz, 2017; Alvarez‐Curto et al., 2016; Bouzo‐Lorenzo et al., 2016; Bradley et al., 2016; Butcher et al., 2011; Butcher et al., 2014; Prihandoko et al., 2016; Zindel et al., 2016).

The phosphorylation sites of α1A‐ and α1D‐adrenoceptors were only recently identifed (Alcantara‐Hernandez et al., 2017;Alfonzo‐Méndez et al., 2018;Carmona‐Rosas et al., 2018). These adrenoceptors are phosphorylated in both the third intracellular loop and C‐tail. Figure 3 illustrates the residues phosphorylated under baseline conditions and after stimulation by agonists or phorbol ester. The large number of phosphorylated residues (18 in α1A‐ and 16 in α1D‐subtypes) and their distribution impose a considerable challenge to define their biological significance. For α1A‐ adrenoceptors, there were differences in the phosphorylation patterns induced by noradrenaline and oxymetazoline (Alcantara‐Hernandez et al., 2017). Not surprisingly, in silico analysis indicated the possible roles for GRK and PKC isoforms, but other kinases may also be involved (Alcantara‐Hernandez et al., 2017; Alfonzo‐Méndez et al., 2018). It is interesting that the phosphorylation sites detected for the α1‐adrenoceptor subtypes are not conserved among them and in only a few cases are the sites are conserved between two subtypes (α1A S250/α1D S323; α1A S258/α1D S334; α1A S407/α1D T507; see Figure 3).

In recombinant systems, α1D‐ adrenoceptors are mainly misfolded or unable to undergo proper ligand binding and intracellularly located due to a motif present within the first N‐terminal 79 amino acids of the receptor (Hague, Chen, et al., 2004; Hague, Uberti, et al., 2004; Pupo, Uberti, & Minneman, 2003). Recent evidence has indicated that N‐terminal proteolysis of the α1D‐ adrenoceptors could be an endogenous mechanism for proper plasma membrane expression (Kountz et al., 2016). To increase membrane expression of this receptor, we used N‐terminally truncated receptors with additional mutations in the third intracellular loop and C‐tail to gain insights on the phosphorylated residues. Among the major findings are the following: noradrenaline increased the intracellular calcium in cells expressing C‐tail truncated α1D‐ adrenoceptors to a similar extent as that seen in cells expressing these receptors with an intact C‐tail (Alfonzo‐Méndez et al., 2016; Alfonzo‐Méndez et al., 2018). In contrast, α1D‐ adrenoceptors in which the phosphorylated residues in the third intracellular loop were replaced by non‐phosphorylatable amino acids presented a markedly decreased calcium response to noradrenaline (Alfonzo‐Méndez et al., 2018). The data indicated that the third loop is important for signalling through G‐protein coupling, as proposed for many GPCRs, and raises the possibility that phosphorylation of these residues might be important for receptor G‐protein activation. The possibility that the C‐tail could also participate in calcium signalling was not discarded, because in cells expressing C‐tail‐truncated α1D‐ adrenoceptors with the third intracellular loop mutated, the calcium response to noradrenaline was decreased even further (Alfonzo‐Méndez et al., 2018; Carmona‐Rosas et al., 2018). ERK 1/2 phosphorylation in cells expressing these mutants was also studied. In cells expressing the control receptor, noradrenaline induced a rapid ERK 1/2 phosphorylation that decreased at 30 and 60 min, whereas in cells with the different mutants, the response was also rapid but either decreased much more slowly or remained elevated during the entire 60 min (Alfonzo‐Méndez et al., 2018; Carmona‐Rosas et al., 2018). This indicates that some of the phosphorylated residues, in both the third intracellular loop and C‐tail, might participate in turning off the signal in the MAPK pathway (Alfonzo‐Méndez et al., 2018; Carmona‐Rosas et al., 2018).

An important additional finding was that although C‐tail‐truncated α1D‐ adrenoceptors were able to mobilize calcium in response to noradrenaline, they were mainly detected in intracellular vesicles, and only a minor fraction was detected at the plasma membrane (Alfonzo‐Méndez et al., 2016; Alfonzo‐Méndez et al., 2018; Carmona‐Rosas et al., 2018). The mutation of a motif in the C‐tail of the α1D‐ adrenoceptors which interacts with the post synaptic density protein (PSD95)/drosophila disc large tumour suppressor/zonula occludens‐1 protein domain of syntrophins markedly decreased these receptorsat the plasma membrane (Chen, Hague, Hall, & Minneman, 2006). Furthermore, it has been observed that the knockout of syntrophins results in the loss of α1D‐adrenoceptor function in mouse aortic smooth muscle cells and the block of α1D‐ adrenoceptor‐mediated increases in BP in mice (Lyssand et al., 2008). These data support a role for the C‐tail of the α1D‐ adrenoceptors, not only in post‐transcriptional regulation by phosphorylation but also in proper receptor insertion in the membrane.

5. ASSOCIATION OF α1‐ADRENOCEPTORS WITH RAB PROTEINS

GPCRs are synthesized and properly folded in the rough endoplasmic reticulum, from where they reach the plasma membrane via intracellular traffic (anterograde transport). GPCRs are transported to the intracellular compartment (retrograde transport) and recycled back to the plasma membrane through constitutive and signal‐triggered internalization and externalization processes. These latter events can take place several times until the GPCRs are degraded in the lysosome or proteasome. Therefore, interaction with proteins that govern traffic is critical, and the signatures that define receptors' destinations are far from completely known. Rab proteins are among the master modulators of vesicular traffic. These comprise a large family of more than 60 monomeric GTPases that favour docking, fusion, cargo exchange, and vesicle transport along the cytoskeleton through interactions with the cytoplasmic face of vesicles with the aid of molecular motors (Hutagalung & Novick, 2011; Schwartz, Cao, Pylypenko, Rak, & Wandinger‐Ness, 2007; Stenmark, 2009; Zerial & McBride, 2001).

Anterograde GPCR traffic has been studied by several groups, particularly that of Wang, Wei, and Wu (2018) and Wang and Wu (2012). Rab1, 2, and 6 modulate GPCR transit from the endoplasmic reticulum to the Golgi, whereas Rab8 and some ARF GTPases regulate the transfer to the plasma membrane (Wang et al., 2018; Wang & Wu, 2012). The anterograde traffic of α1‐adrenoceptors has also been studied, and it has been observed that the attenuation of Rab1 function inhibits the transit of α1A‐ and α1B‐adrenoceptors to the plasma membrane, whereas augmented Raf1 function increases transit (Filipeanu, Zhou, Fugetta, & Wu, 2006; Wang & Wu, 2012). In addition, the overexpression of Rab1 selectively enhances ERK 1/2 activation and leads to cardiomyocyte hypertrophy in response to phenylephrine (Filipeanu et al., 2006).

To the best of our knowledge, the role of Rab proteins in the retrograde transport of α1B‐adrenoceptors was only recently reported. Agonist‐activated α1B‐adrenoceptors (associated with homologous desensitization) mainly interacted with proteins present in early endosomes, such as early endosome antigen 1, Rab5, Rab4, and Rab11, but not with the late endosome markers Rab9 and Rab7 (Alfonzo‐Méndez et al., 2017; Castillo‐Badillo et al., 2015). In contrast, the activation of other receptors (such as sphingosine 1‐phosphate receptors) or direct activation of PKC by phorbol esters (heterologous desensitization) induced a brief α1B‐adrenoceptor–Rab5 interaction, a more pronounced and sustained one with Rab9, and some interaction with Rab7 (Alfonzo‐Méndez, Hernández‐Espinosa, et al., 2017; Castillo‐Badillo et al., 2015). It is worth mentioning that the action of sphingosine‐1‐phosphate on the phosphorylation/desensitization/internalization of α1B‐adrenoceptors mainly depended on the activation of PKC (Alfonzo‐Méndez, Hernández‐Espinosa, et al., 2017). These data suggested that agonist‐activated α1B‐adrenoceptors undergo rapid internalization and recycling back to the plasma membrane, whereas heterologous desensitization was associated with a slower recycling pathway. However, preliminary work with non‐adrenergic receptors indicates that although some similarities might exist with internalization and Rab protein association to other GPCRs, the findings with the α1B‐adrenoceptors cannot be generalized; in fact, different Rab protein association was observed using different agonists for the same receptor (García‐Sáinz et al., 2016 unpublished observations). A major question arises from these observations regarding the nature of the “signal” or “tag” that defines the immediate destiny of a given receptor, that is, is the receptor interaction with a given Rab protein defined by conformational changes induced by the distinct ligands, by covalent (receptor phosphorylation, palmitoylation, or other) or non‐covalent modifications, or by all of these? Our current hypothesis is that the so‐called phosphorylation “barcode” (Tobin, 2008; Tobin et al., 2008) could be a major participant.

6. DESENSITIZATION AND INTERNALIZATION OF α1‐ADRENOCEPTORS

Receptor desensitization, a decreased cell responsiveness to agonists, has been operationally divided into homologous and heterologous types. In homologous desensitization, the decreased responsiveness results from the previous activation of the same receptor affected, whereas in heterologous desensitization, the decreased responsiveness is not limited to the previously activated receptor type and may result from the activation of protein kinases and other molecular entities. The present review emphasizes the mechanisms involved in the homologous desensitization of α1‐adrenoceptors.

The interaction of α1‐adrenoceptors with proteins such as β‐arrrestins and other molecular entities during these processes has been reported, and readers are directed to those publications (Cotecchia, Stanasila, & Diviani, 2012; Perez‐Aso et al., 2013; Segura et al., 2013; Stanasila, Abuin, Dey, & Cotecchia, 2008).

There are significant differences in the degrees of desensitization and in the kinetics of internalization among the α1‐adrenoceptors. Studies comparing the internalization of these receptors in the same cellular background have shown that α1B‐ and α1D‐ adrenoceptors activated by noradrenaline, adrenaline, or phenylephrine internalize at a much faster rate than the α1A‐ adrenoceptors (Cabrera‐Wrooman, Romero‐Avila, & Garcia‐Sainz, 2010; Chalothorn et al., 2002; Stanasila et al., 2008; Wang et al., 2007). Conversely, the α1A‐ adrenoceptors were much more resistant to desensitization induced by noradrenaline or phorbol ester than were the α1B‐ and α1D‐ adrenoceptors (Cabrera‐Wrooman et al., 2010; Vazquez‐Prado et al., 2000; Vazquez‐Prado & Garcia‐Sainz, 1996). Therefore, the general view is that the α1A‐ adrenoceptors are less tightly regulated than the other two subtypes (Cotecchia, 2010).

More recent studies have shown that the α1A‐ adrenoceptors can indeed undergo fast desensitization and internalization, but this depends on the agonist activating the receptor. In HEK293 cells, α1A‐ adrenoceptors activated by oxymetazoline internalized at a much faster rate (~5 min) than when activated by noradrenaline (>45 min; Akinaga et al., 2013). Moreover, there was significant tachyphylaxis in the contractions of smooth muscles in response to oxymetazoline, whereas no tachyphylaxis was observed for noradrenaline. In addition, short exposures of cells or tissues to oxymetazoline (5 min) reduced the potency of noradrenaline in a subsequent exposure (Akinaga et al., 2013; Alcantara‐Hernandez et al., 2017). The phosphorylation and faster desensitization/internalization of the α1A‐ adrenoceptors activated by oxymetazoline largely depended on GRK2, whereas the phosphorylation and slower desensitization/internalization produced by noradrenaline depended on PKCα. In LNCap cells, the co‐localization and co‐immunoprecipitation of α1A‐ adrenoceptors and β‐arrestin produced by oxymetazoline was as strong as those produced by noradrenaline, despite the weak partial agonism of oxymetazoline for Ca2+ mobilization (Alcantara‐Hernandez et al., 2017). Strikingly, oxymetazoline was more efficacious and potent than noradrenaline for the phosphorylation of ERK 1/2 in LNCap cells but differed from what was observed in HEK293 cells (da Silva Junior et al., 2017). The superagonism of oxymetazoline for the ERK pathway in LNCap cells was unrelated to 5‐HT receptor activation and was antagonized by prazosin (Alcantara‐Hernandez et al., 2017). One of the most accentuated manifestations of biased agonism is the reversal in the order of potencies and/or efficacies for agonists in the production of different effects mediated by a receptor (Kenakin & Christopoulos, 2013; Pupo et al., 2016). This is a clear example of efficacy reversal and therefore of the biased agonism for oxymetazoline towards the ERK pathway versus Ca2+ mobilization at the α1A‐ adrenoceptors.

Analysis of the phosphorylated α1A‐ adrenoceptors activated by oxymetazoline and noradrenaline in LNCap cells revealed that two residues located in the C‐tail (S381 and T384; see Figure 3) were exclusively phosphorylated when the receptor was activated by oxymetazoline, implicating this region in the differential effects of these two agonists (Alcantara‐Hernandez et al., 2017). On the other hand, there were residues that were exclusively phosphorylated when the α1A‐ adrenoceptors were activated by noradrenaline (S220 and S229), and these are in the beginning of the third intracellular loop. Therefore, depending on the agonist, clearly distinct phosphorylation barcodes are formed in these adrenoceptors.

The understanding of the phosphorylation barcoding produced by different ligands and their functional repercussions may provide the rationale for the development of α1‐adrenoceptor ligands more suited to some needed therapeutic purposes, such as less tachyphylactic ligands for more sustained rises in BP for the treatment of shock or vasoconstrictors without rebound effects.

7. CONCLUDING REMARKS

In these nearly 45 years since the pharmacological separation of α1‐adrenoceptors from the α2‐adrenoceptors (Dubocovich & Langer, 1974; Langer, 1974; Starke, Montel, Gayk, & Merker, 1974) and 30 years after the cloning of the first α1‐adrenoceptor (the hamster α1B‐adrenoceptor; Cotecchia et al., 1988; for a historical perspective, see Langer, 1999), considerable progress has been made towards the understanding of the physiological roles of the α1‐adrenoceptor subtypes and their recognition as well as regulation by drugs. This knowledge translated into a few drugs that are safe and efficacious; the most relevant of them in our opinion being the so‐called α‐blockers for BPH and other micturition dysfunctions, which benefit a large proportion of the human population at some point in their lives.

The array of functions controlled by α1‐adrenoceptors has not been completely covered in this review, but enough has been presented to demonstrate the immense potential of these subtypes for innovative pharmacological interventions. The discoveries during the past two decades showing that drugs do not fit into simple agonist or antagonist categories and that receptors can regulate multiple signalling pathways further encourage the search for new drugs that target the α1‐adrenoceptor subtypes for new therapeutic purposes. For the success of this endeavour, continuous effort and sharp pharmacological reasoning are essential.

7.1. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander, S. P. H., Christopoulos et al., 2017; Alexander, Cidlowski et al., 2017; Alexander, Fabbro et al., 2017; Alexander, Peters et al., 2017).

CONFLICT OF INTEREST

The authors declare no conflicts of interest

ACKNOWLEDGEMENTS

Research in JAG's laboratory is supported by Grants from Consejo Nacional de Ciencia y Tecnología (CONACYT) [Grant 253156 and FDC‐882] and Dirección General de Personal Académico‐UNAM [PAPIIT, Grant IN200915]. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – 23038.007773/2014‐07, as J.A. received a CAPES Drug Discovery fellowship and during the preparation of this review was at the University of Nottingham, UK. Research in ASP's laboratory is supported by Grants from Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP [2008/50423‐7 and 2017/15175‐1]. The authors are thankful to Dr. Vanessa Lima for kindly providing Figure 1.

Akinaga J, García‐Sáinz JA, S. Pupo A. Updates in the function and regulation of α1‐adrenoceptors. Br J Pharmacol. 2019;176:2343–2357. 10.1111/bph.14617

REFERENCES

  1. Akinaga, J. , Lima, V. , Kiguti, L. R. , Hebeler‐Barbosa, F. , Alcantara‐Hernandez, R. , Garcia‐Sainz, J. A. , & Pupo, A. S . (2013). Differential phosphorylation, desensitization, and internalization of α1A‐adrenoceptors activated by norepinephrine and oxymetazoline. Molecular Pharmacology, 83(4), 870–881. 10.1124/mol.112.082313 [DOI] [PubMed] [Google Scholar]
  2. Alcantara‐Hernandez, R. , Hernandez‐Mendez, A. , Romero‐Avila, M. T. , Alfonzo‐Mendez, M. A. , Pupo, A. S. , & Garcia‐Sainz, J. A. (2017). Noradrenaline, oxymetazoline and phorbol myristate acetate induce distinct functional actions and phosphorylation patterns of α1A‐adrenergic receptors. Biochimica et Biophysica Acta, 1864(12), 2378–2388. 10.1016/j.bbamcr.2017.09.002 [DOI] [PubMed] [Google Scholar]
  3. Alexander, S. P. H. , Christopoulos, A. , Davenport, A. P. , Kelly, E. , Marrion, N. V. , Peters, J. A. , … CGTP Collaborators (2017). The Concise Guide to PHARMACOLOGY 2017/18: G protein‐coupled receptors. British Journal of Pharmacology, 174, S17–S129. 10.1111/bph.13878 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alexander, S. P. H. , Cidlowski, J. A. , Kelly, E. , Marrion, N. V. , Peters, J. A. , Faccenda, E. , … CGTP Collaborators (2017). The Concise Guide to PHARMACOLOGY 2017/18: Nuclear hormone receptors. British Journal of Pharmacology, 174, S208–S224. 10.1111/bph.13880 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Marrion, N. V. , Peters, J. A. , Faccenda, E. , … CGTP Collaborators (2017). The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. British Journal of Pharmacology, 174, S272–S359. 10.1111/bph.13877 [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Alexander, S. P. H. , Peters, J. A. , Kelly, E. , Marrion, N. V. , Faccenda, E. , Harding, S. D. , … CGTP Collaborators (2017). The Concise Guide to PHARMACOLOGY 2017/18: Ligand‐gated ion channels. British Journal of Pharmacology, 174, S130–S159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Alexandre, E. C. , de Oliveira, M. G. , Campos, R. , Kiguti, L. R. , Calmasini, F. B. , Silva, F. H. , … Antunes, E. (2017). How important is the α1‐adrenoceptor in primate and rodent proximal urethra? Sex differences in the contribution of α1‐adrenoceptor to urethral contractility. American Journal of Physiology. Renal Physiology, 312(6), F1026–F1034. 10.1152/ajprenal.00013.2017 [DOI] [PubMed] [Google Scholar]
  8. Alfonzo‐Méndez, M. A. , Alcántara‐Hernández, R. , & García‐Sáinz, J. A. (2017). Novel structural approaches to study GPCR regulation. International Journal of Molecular Sciences, 18, 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Alfonzo‐Méndez, M. A. , Carmona‐Rosas, G. , Hernández‐Espinosa, D. A. , Romero‐Ávila, M. T. , & García‐Sáinz, J. A. (2018). Different phosphorylation patterns regulate α1D‐adrenoceptor signaling and desensitization. Biochimica et Biophysica Acta, 1865(6), 842–854. [DOI] [PubMed] [Google Scholar]
  10. Alfonzo‐Méndez, M. A. , Castillo‐Badillo, J. A. , Romero‐Ávila, M. T. , Rivera, R. , Chun, J. , & García‐Sáinz, J. A. (2016). Carboxyl terminus‐truncated α1D‐adrenoceptors inhibit the ERK pathway. Naunyn‐Schmiedeberg's Archives of Pharmacology, 389(8), 911–920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Alfonzo‐Méndez, M. A. , Hernández‐Espinosa, D. A. , Carmona‐Rosas, G. , Romero‐Ávila, M. T. , Reyes‐Cruz, G. , & García‐Sáinz, J. A. (2017). Protein kinase C activation promotes α1B‐adrenoceptor internalization and late endosome trafficking through Rab9 interaction. Role in heterologous desensitization. Molecular Pharmacology, 91(4), 296–306. [DOI] [PubMed] [Google Scholar]
  12. Alvarez‐Curto, E. , Inoue, A. , Jenkins, L. , Raihan, S. Z. , Prihandoko, R. , Tobin, A. B. , & Milligan, G. (2016). Targeted elimination of G proteins and arrestins defines their specific contributions to both intensity and duration of G protein‐coupled receptor signaling. The Journal of Biological Chemistry, 291(53), 27147–27159. 10.1074/jbc.M116.754887 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Arce, C. , Vicente, D. , Segura, V. , Flacco, N. , Monto, F. , Almenar, L. , … Ivorra, M. D. (2017). Activation of alpha1A‐adrenoceptors desensitizes the rat aorta response to phenylephrine through a neuronal NOS pathway, a mechanism lost with ageing. British Journal of Pharmacology, 174(13), 2015–2030. 10.1111/bph.13800 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Arevalo‐Leon, L. E. , Gallardo‐Ortiz, I. A. , Urquiza‐Marin, H. , & Villalobos‐Molina, R. (2003). Evidence for the role of alpha1D‐ and alpha1A‐adrenoceptors in contraction of the rat mesenteric artery. Vascular Pharmacology, 40(2), 91–96. 10.1016/S1537-1891(02)00336-1 [DOI] [PubMed] [Google Scholar]
  15. Avellar, M. C. , Lazari, M. F. , & Porto, C. S. (2009). Expression and function of G‐protein‐coupled receptors in the male reproductive tract. Anais da Academia Brasileira de Ciências, 81(3), 321–344. 10.1590/S0001-37652009000300002 [DOI] [PubMed] [Google Scholar]
  16. Bexis, S. , Cleary, L. , McGrath, J. C. , Tanoue, A. , Tsujimoto, G. , & Docherty, J. R. (2008). Alpha(1D)‐adrenoceptors mediate nerve and agonist‐evoked contractions in mouse vas deferens: Evidence obtained from knockout technology. Autonomic & Autacoid Pharmacology, 28(2–3), 81–85. 10.1111/j.1474-8673.2008.00420.x [DOI] [PubMed] [Google Scholar]
  17. Bouzo‐Lorenzo, M. , Santo‐Zas, I. , Lodeiro, M. , Nogueiras, R. , Casanueva, F. F. , Castro, M. , … Camiña, J. P. (2016). Distinct phosphorylation sites on the ghrelin receptor, GHSR1a, establish a code that determines the functions of ss‐arrestins. Scientific Reports, 6, 22495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Bradley, S. J. , Wiegman, C. H. , Iglesias, M. M. , Kong, K. C. , Butcher, A. J. , Plouffe, B. , … Tobin, A. B. (2016). Mapping physiological G protein‐coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction. Proceedings of the National Academy of Sciences of the United States of America, 113(16), 4524–4529. 10.1073/pnas.1521706113 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bulloch, J. M. , & Daly, C. J. (2014). Autonomic nerves and perivascular fat: Interactive mechanisms. Pharmacology & Therapeutics, 143(1), 61–73. [DOI] [PubMed] [Google Scholar]
  20. Burt, R. P. , Chapple, C. R. , & Marshall, I. (1995). Evidence for a functional alpha 1A‐(alpha 1C‐) adrenoceptor mediating contraction of the rat epididymal vas deferens and an alpha 1B‐adrenoceptor mediating contraction of the rat spleen. British Journal of Pharmacology, 115(3), 467–475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Butcher, A. J. , Hudson, B. D. , Shimpukade, B. , Alvarez‐Curto, E. , Prihandoko, R. , Ulven, T. , … Tobin, A. B. (2014). Concomitant action of structural elements and receptor phosphorylation determine arrestin‐3 interaction with the free fatty acid receptor FFA4. The Journal of Biological Chemistry, 289(26), 18451–18465. 10.1074/jbc.M114.568816 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Butcher, A. J. , Prihandoko, R. , Kong, K. C. , McWilliams, P. , Edwards, J. M. , Bottrill, A. , … Tobin, A. B. (2011). Differential G‐protein‐coupled receptor phosphorylation provides evidence for a signaling bar code. The Journal of Biological Chemistry, 286(13), 11506–11518. 10.1074/jbc.M110.154526 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Cabrera‐Wrooman, A. , Romero‐Avila, M. T. , & Garcia‐Sainz, J. A. (2010). Roles of the alpha1A‐adrenergic receptor carboxyl tail in protein kinase C‐induced phosphorylation and desensitization. Naunyn‐Schmiedeberg's Archives of Pharmacology, 382(5–6), 499–510. 10.1007/s00210-010-0569-7 [DOI] [PubMed] [Google Scholar]
  24. Carmona‐Rosas, G. , Hernández‐Espinosa, D. A. , Alcántara‐Hernández, R. , Alfonzo‐Méndez, M. A. , & García‐Sáinz, J. A. (2018). Distinct phosphorylation sites/clusters in the carboxyl terminus regulate α1D‐adrenergic receptor subcellular localization and signaling. Cellular Signalling, 53, 374–389. [DOI] [PubMed] [Google Scholar]
  25. Castillo‐Badillo, J. A. , Sánchez‐Reyes, O. B. , Alfonzo‐Méndez, M. A. , Romero‐Ávila, M. T. , Reyes‐Cruz, G. , & García‐Sáinz, J. A. (2015). α1B‐Adrenergic receptors differentially associate with Rab proteins during homologous and heterologous desensitization. PLoS ONE, 10(3), e0121165 10.1371/journal.pone.0121165 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Cavalli, A. , Lattion, A. L. , Hummler, E. , Nenniger, M. , Pedrazzini, T. , Aubert, J. F. , … Cotecchia, S. (1997). Decreased blood pressure response in mice deficient of the alpha1b‐adrenergic receptor. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 11589–11594. 10.1073/pnas.94.21.11589 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Chagas‐Silva, F. , Nascimento‐Viana, J. B. , Romeiro, L. A. , Barberato, L. C. , Noel, F. , & Silva, C. L. (2014). Pharmacological characterization of N1‐(2‐methoxyphenyl)‐N4‐hexylpiperazine as a multi‐target antagonist of α1A/α1D‐adrenoceptors and 5‐HT1A receptors that blocks prostate contraction and cell growth. Naunyn‐Schmiedeberg's Archives of Pharmacology, 387(3), 225–234. 10.1007/s00210-013-0935-3 [DOI] [PubMed] [Google Scholar]
  28. Chalothorn, D. , McCune, D. F. , Edelmann, S. E. , Garcia‐Cazarin, M. L. , Tsujimoto, G. , & Piascik, M. T. (2002). Differences in the cellular localization and agonist‐mediated internalization properties of the alpha(1)‐adrenoceptor subtypes. Molecular Pharmacology, 61(5), 1008–1016. [DOI] [PubMed] [Google Scholar]
  29. Chen, Z. , Hague, C. , Hall, R. A. , & Minneman, K. P. (2006). Syntrophins regulate alpha1D‐adrenergic receptors through a PDZ domain‐mediated interaction. The Journal of Biological Chemistry, 281(18), 12414–12420. [DOI] [PubMed] [Google Scholar]
  30. Cleary, L. , Slattery, J. , Bexis, S. , & Docherty, J. R. (2004). Sympathectomy reveals alpha 1A‐ and alpha 1D‐adrenoceptor components to contractions to noradrenaline in rat vas deferens. British Journal of Pharmacology, 143(6), 745–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Cohen, P. (2002). The origins of protein phosphorylation. Nature Cell Biology, 4(5), E127–E130. [DOI] [PubMed] [Google Scholar]
  32. Colling, K. P. , Banton, K. L. , & Beilman, G. J. (2018). Vasopressors in sepsis. Surgical Infections, 19(2), 202–207. 10.1089/sur.2017.255 [DOI] [PubMed] [Google Scholar]
  33. Corvera, S. , & García‐Sáinz, J. A. (1984). Phorbol esters inhibit alpha1 adrenergic stimulation of glycogenolysis in isolated rat hepatocytes. Biochemical and Biophysical Research Communications, 119(3), 1128–1133. 10.1016/0006-291X(84)90892-1 [DOI] [PubMed] [Google Scholar]
  34. Cotecchia, S. (2007). Constitutive activity and inverse agonism at the alpha1adrenoceptors. Biochemical Pharmacology, 73(8), 1076–1083. 10.1016/j.bcp.2006.10.024 [DOI] [PubMed] [Google Scholar]
  35. Cotecchia, S. (2010). The α1‐adrenergic receptors: Diversity of signaling networks and regulation. Journal of Receptor and Signal Transduction Research, 30(6), 410–419. 10.3109/10799893.2010.518152 [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Cotecchia, S. , Del Vescovo, C. D. , Colella, M. , Caso, S. , & Diviani, D. (2015). The alpha1‐adrenergic receptors in cardiac hypertrophy: Signaling mechanisms and functional implications. Cellular Signalling, 27(10), 1984–1993. 10.1016/j.cellsig.2015.06.009 [DOI] [PubMed] [Google Scholar]
  37. Cotecchia, S. , Scheer, A. , Diviani, D. , Fanelli, F. , & De Benedetti, P. G. (1998). Molecular mechanisms involved in the activation and regulation of the alpha 1‐adrenergic receptor subtypes. Farmaco, 53(4), 273–277. 10.1016/S0014-827X(98)00021-4 [DOI] [PubMed] [Google Scholar]
  38. Cotecchia, S. , Schwinn, D. A. , Randall, R. R. , Lefkowitz, R. J. , Caron, M. G. , & Kobilka, B. K. (1988). Molecular cloning and expression of the cDNA for the hamster alpha 1‐adrenergic receptor. Proceedings of the National Academy of Sciences of the United States of America, 85(19), 7159–7163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Cotecchia, S. , Stanasila, L. , & Diviani, D. (2012). Protein–protein interactions at the adrenergic receptors. Current Drug Targets, 13(1), 15–27. 10.2174/138945012798868489 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Cotecchia, S. , Stanasila, L. , Diviani, D. , Bjorklof, K. , Rossier, O. , & Fanelli, F. (2004). Structural determinants involved in the activation and regulation of G protein‐coupled receptors: Lessons from the alpha1‐adrenegic receptor subtypes. Biology of the Cell, 96(5), 327–333. 10.1111/j.1768-322X.2004.tb01422.x [DOI] [PubMed] [Google Scholar]
  41. Cowley, P. M. , Wang, G. , Joshi, S. , Swigart, P. M. , Lovett, D. H. , Simpson, P. C. , & Baker, A. J. (2017). α1A‐Subtype adrenergic agonist therapy for the failing right ventricle. American Journal of Physiology. Heart and Circulatory Physiology, 313(6), H1109–H1118. 10.1152/ajpheart.00153.2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Dahl, E. F. , Wu, S. C. , Healy, C. L. , Harsch, B. A. , Shearer, G. C. , & O'Connell, T. D. (2018). Subcellular compartmentalization of proximal Galphaq‐receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes. The Journal of Biological Chemistry, 293(23), 8734–8749. 10.1074/jbc.RA118.002283 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Daly, C. J. , Deighan, C. , McGee, A. , Mennie, D. , Ali, Z. , McBride, M. , & McGrath, J. C. (2002). A knockout approach indicates a minor vasoconstrictor role for vascular alpha1B‐adrenoceptors in mouse. Physiological Genomics, 9(2), 85–91. 10.1152/physiolgenomics.00065.2001 [DOI] [PubMed] [Google Scholar]
  44. de Andrade, C. R. , Fukada, S. Y. , Olivon, V. C. , de Godoy, M. A. , Haddad, R. , Eberlin, M. N. , … de Oliveira, A. M. (2006). Alpha1D‐adrenoceptor‐induced relaxation on rat carotid artery is impaired during the endothelial dysfunction evoked in the early stages of hyperhomocysteinemia. European Journal of Pharmacology, 543(1–3), 83–91. [DOI] [PubMed] [Google Scholar]
  45. Diviani, D. , Lattion, A. L. , & Cotecchia, S. (1997). Characterization of the phosphorylation sites involved in G protein‐coupled receptor kinase‐ and protein kinase C‐mediated desensitization of the alpha1B‐adrenergic receptor. The Journal of Biological Chemistry, 272(45), 28712–28719. [DOI] [PubMed] [Google Scholar]
  46. Diviani, D. , Lattion, A. L. , Larbi, N. , Kunapuli, P. , Pronin, A. , Benovic, J. L. , & Cotecchia, S. (1996). Effect of different G protein‐coupled receptor kinases on phosphorylation and desensitization of the alpha1B‐adrenergic receptor. The Journal of Biological Chemistry, 271(9), 5049–5058. [DOI] [PubMed] [Google Scholar]
  47. Docherty, J. R. (2010). Subtypes of functional alpha1‐adrenoceptor. Cellular and Molecular Life Sciences: CMLS, 67(3), 405–417. 10.1007/s00018-009-0174-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Dubocovich, M. L. , & Langer, S. Z. (1974). Negative feed‐back regulation of noradrenaline release by nerve stimulation in the perfused cat's spleen: Differences in potency of phenoxybenzamine in blocking the pre‐ and post‐synaptic adrenergic receptors. The Journal of Physiology, 237(3), 505–519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Erami, C. , Zhang, H. , Ho, J. G. , French, D. M. , & Faber, J. E. (2002). Alpha(1)‐adrenoceptor stimulation directly induces growth of vascular wall in vivo. American Journal of Physiology. Heart and Circulatory Physiology, 283(4), H1577–H1587. 10.1152/ajpheart.00218.2002 [DOI] [PubMed] [Google Scholar]
  50. Faber, J. E. , Szymeczek, C. L. , Cotecchia, S. , Thomas, S. A. , Tanoue, A. , Tsujimoto, G. , & Zhang, H. (2007). Alpha1‐adrenoceptor‐dependent vascular hypertrophy and remodeling in murine hypoxic pulmonary hypertension. American Journal of Physiology. Heart and Circulatory Physiology, 292(5), H2316–H2323. 10.1152/ajpheart.00792.2006 [DOI] [PubMed] [Google Scholar]
  51. Faure, C. , Pimoule, C. , Vallancien, G. , Langer, S. Z. , & Graham, D. (1994). Identification of alpha 1‐adrenoceptor subtypes present in the human prostate. Life Sciences, 54(21), 1595–1605. 10.1016/0024-3205(94)90031-0 [DOI] [PubMed] [Google Scholar]
  52. Filipeanu, C. M. , Zhou, F. , Fugetta, E. K. , & Wu, G. (2006). Differential regulation of the cell‐surface targeting and function of beta‐ and alpha1‐adrenergic receptors by Rab1 GTPase in cardiac myocytes. Molecular Pharmacology, 69(5), 1571–1578. 10.1124/mol.105.019984 [DOI] [PubMed] [Google Scholar]
  53. Filippi, S. , Parenti, A. , Donnini, S. , Granger, H. J. , Fazzini, A. , & Ledda, F. (2001). Alpha(1D)‐adrenoceptors cause endothelium‐dependent vasodilatation in the rat mesenteric vascular bed. The Journal of Pharmacology and Experimental Therapeutics, 296(3), 869–875. [PubMed] [Google Scholar]
  54. Flacco, N. , Pares, J. , Serna, E. , Segura, V. , Vicente, D. , Perez‐Aso, M. , … D'Ocon, P . (2013). Alpha1D‐adrenoceptors are responsible for the high sensitivity and the slow time‐course of noradrenaline‐mediated contraction in conductance arteries. Pharmacology Research & Perspectives, 1(1), e00001 10.1002/prp2.1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Forray, C. , Bard, J. A. , Wetzel, J. M. , Chiu, G. , Shapiro, E. , Tang, R. , et al. (1994). The alpha 1‐adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype. Molecular Pharmacology, 45(4), 703–708. [PubMed] [Google Scholar]
  56. Fredriksson, R. , Lagerstrom, M. C. , Lundin, L. G. , & Schioth, H. B. (2003). The G‐protein‐coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Molecular Pharmacology, 63(6), 1256–1272. [DOI] [PubMed] [Google Scholar]
  57. Fredriksson, R. , & Schioth, H. B. (2005). The repertoire of G‐protein‐coupled receptors in fully sequenced genomes. Molecular Pharmacology, 67(5), 1414–1425. 10.1124/mol.104.009001 [DOI] [PubMed] [Google Scholar]
  58. Gallardo‐Ortiz, I. A. , Rodriguez‐Hernandez, S. N. , Lopez‐Guerrero, J. J. , Del Valle‐Mondragon, L. , Lopez‐Sanchez, P. , Touyz, R. M. , & Villalobos‐Molina, R. (2015). Role of alpha1D‐adrenoceptors in vascular wall hypertrophy during angiotensin II‐induced hypertension. Autonomic & Autacoid Pharmacology, 35(3), 17–31. 10.1111/aap.12035 [DOI] [PubMed] [Google Scholar]
  59. García‐Sáinz, J. A. , Rodríguez‐Pérez, C. E. , & Romero‐Ávila, M. T. (2004). Human alpha‐1D adrenoceptor phosphorylation and desensitization. Biochemical Pharmacology, 67, 1853–1858. [DOI] [PubMed] [Google Scholar]
  60. García‐Sáinz, J. A. , Romero‐Ávila, M. T. , & Alcántara‐Hernández, R. (2011). Mechanisms involved in alpha(1B)‐adrenoceptor desensitization. IUBMB Life, 63, 811–815. 10.1002/iub.519 [DOI] [PubMed] [Google Scholar]
  61. García‐Sáinz, J. A. , & Torres‐Padilla, M. E. (1999). Modulation of basal intracellular calcium by inverse agonists and phorbol myristate acetate in rat‐1 fibroblasts stably expressing alpha1d‐adrenoceptors. FEBS Letters, 443(3), 277–281. 10.1016/S0014-5793(98)01738-4 [DOI] [PubMed] [Google Scholar]
  62. García‐Sáinz, J. A. , Vázquez‐Cuevas, F. G. , & Romero‐Ávila, M. T. (2001). Phosphorylation and desensitization of alpha1d‐adrenergic receptors. The Biochemical Journal, 353(Pt 3), 603–610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. García‐Sáinz, J. A. , Vázquez‐Prado, J. , & Medina, L. C. (2000). Alpha 1‐adrenoceptors: Function and phosphorylation. European Journal of Pharmacology, 389(1), 1–12. [DOI] [PubMed] [Google Scholar]
  64. Garcia‐Sainz, J. A. , Vazquez‐Prado, J. , & Villalobos‐Molina, R. (1999). Alpha 1‐adrenoceptors: Subtypes, signaling, and roles in health and disease. Archives of Medical Research, 30(6), 449–458. [DOI] [PubMed] [Google Scholar]
  65. Geloen, A. , Pichot, C. , Leroy, S. , Julien, C. , Ghignone, M. , May, C. N. , & Quintin, L. (2015). Pressor response to noradrenaline in the setting of septic shock: Anything new under the sun‐dexmedetomidine, clonidine? A minireview. BioMed Research International, 2015, 863715 10.1155/2015/863715 [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Gisbert, R. , Noguera, M. A. , Ivorra, M. D. , & D'Ocon, P. (2000). Functional evidence of a constitutively active population of alpha(1D)‐adrenoceptors in rat aorta. The Journal of Pharmacology and Experimental Therapeutics, 295(2), 810–817. [PubMed] [Google Scholar]
  67. Gisbert, R. , Ziani, K. , Miquel, R. , Noguera, M. A. , Ivorra, M. D. , Anselmi, E. , & D'Ocon, P. (2002). Pathological role of a constitutively active population of alpha(1D)‐adrenoceptors in arteries of spontaneously hypertensive rats. British Journal of Pharmacology, 135(1), 206–216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Hague, C. , Chen, Z. , Pupo, A. S. , Schulte, N. A. , Toews, M. L. , & Minneman, K. P. (2004). The N terminus of the human {alpha}1D‐adrenergic receptor prevents cell surface expression. The Journal of Pharmacology and Experimental Therapeutics, 309(1), 388–397. [DOI] [PubMed] [Google Scholar]
  69. Hague, C. , Uberti, M. A. , Chen, Z. , Hall, R. A. , & Minneman, K. P. (2004). Cell surface expression of {alpha}1D‐adrenergic receptors is controlled by heterodimerization with {alpha}1B‐adrenergic receptors. The Journal of Biological Chemistry, 279(15), 15541–15549. 10.1074/jbc.M314014200 [DOI] [PubMed] [Google Scholar]
  70. Harding, S. D. , Sharman, J. L. , Faccenda, E. , Southan, C. , Pawson, A. J. , Ireland, S. , … NC‐IUPHAR . (2018). The IUPHAR/BPS guide to PHARMACOLOGY in 2018: Updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Research, 46(D1), D1091–D1106. 10.1093/nar/gkx1121 [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Hieble, J. P. , Bylund, D. B. , Clarke, D. E. , Eikenburg, D. C. , Langer, S. Z. , Lefkowitz, R. J. , … Ruffolo, R. R. Jr. (1995). International Union of Pharmacology. X. Recommendation for nomenclature of alpha 1‐adrenoceptors: Consensus update. Pharmacological Reviews, 47(2), 267–270. [PubMed] [Google Scholar]
  72. Hrometz, S. L. , Edelmann, S. E. , McCune, D. F. , Olges, J. R. , Hadley, R. W. , Perez, D. M. , & Piascik, M. T. (1999). Expression of multiple alpha1‐adrenoceptors on vascular smooth muscle: Correlation with the regulation of contraction. The Journal of Pharmacology and Experimental Therapeutics, 290(1), 452–463. [PubMed] [Google Scholar]
  73. Hussain, M. B. , & Marshall, I. (1997). Characterization of alpha1‐adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery. British Journal of Pharmacology, 122(5), 849–858. 10.1038/sj.bjp.0701461 [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Hutagalung, A. H. , & Novick, P. J. (2011). Role of Rab GTPases in membrane traffic and cell physiology. Physiological Reviews, 91(1), 119–149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Hwang, T. L. , Lau, Y. T. , Huang, S. F. , Chen, M. F. , & Liu, M. S. (1994). Changes of alpha 1‐adrenergic receptors in human liver during intraabdominal sepsis. Hepatology, 20(3), 638–642. 10.1002/hep.1840200314 [DOI] [PubMed] [Google Scholar]
  76. Ibarra, M. , Terrón, J. A. , López‐Guerrero, J. J. , & Villalobos‐Molina, R. (1997). Evidence for an age‐dependent functional expression of alpha 1D‐adrenoceptors in the rat vasculature. European Journal of Pharmacology, 322(2–3), 221–224. [DOI] [PubMed] [Google Scholar]
  77. Jensen, B. C. , O'Connell, T. D. , & Simpson, P. C. (2011). Alpha‐1‐adrenergic receptors: Targets for agonist drugs to treat heart failure. Journal of Molecular and Cellular Cardiology, 51(4), 518–528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Jensen, B. C. , Swigart, P. M. , Montgomery, M. D. , & Simpson, P. C. (2010). Functional alpha‐1B adrenergic receptors on human epicardial coronary artery endothelial cells. Naunyn‐Schmiedeberg's Archives of Pharmacology, 382(5–6), 475–482. 10.1007/s00210-010-0558-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Jentzer, J. C. , Vallabhajosyula, S. , Khanna, A. K. , Chawla, L. S. , Busse, L. W. , & Kashani, K. B. (2018). Management of refractory vasodilatory shock. Chest, 154(2), 416–426. [DOI] [PubMed] [Google Scholar]
  80. Joost, P. , & Methner, A. (2002). Phylogenetic analysis of 277 human G‐protein‐coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biology, 3(11), research0063.1–0063.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Kamikihara, S. Y. , Mueller, A. , Lima, V. , Akinaga, J. , Nojimoto, F. D. , Castilho, A. , … Pupo, A. S. (2007). Alpha1‐adrenoceptors in proximal segments of tail arteries from control and reserpinised rats. Naunyn‐Schmiedeberg's Archives of Pharmacology, 376(1–2), 117–126. [DOI] [PubMed] [Google Scholar]
  82. Kamikihara, S. Y. , Mueller, A. , Lima, V. , Silva, A. R. , da Costa, I. B. , Buratini, J. Jr. , … Pupo, A. S. (2005). Differential distribution of functional alph}1‐adrenergic receptor subtypes along the rat tail artery. The Journal of Pharmacology and Experimental Therapeutics, 314(2), 753–761. 10.1124/jpet.105.087502 [DOI] [PubMed] [Google Scholar]
  83. Kenakin, T. , & Christopoulos, A. (2013). Signalling bias in new drug discovery: Detection, quantification and therapeutic impact. Nature reviews. Drug Discovery, 12(3), 205–216. 10.1038/nrd3954. [DOI] [PubMed] [Google Scholar]
  84. Kircik, L. H. , DuBois, J. , Draelos, Z. D. , Werschler, P. , Grande, K. , Cook‐Bolden, F. E. , … Ahluwalia, G. (2018). pivotal trial of the efficacy and safety of oxymetazoline cream 1.0% for the treatment of persistent facial erythema associated with rosacea: Findings from the first REVEAL trial. Journal of Drugs in Dermatology: JDD, 17(1), 97–105. [PubMed] [Google Scholar]
  85. Koshimizu, T. A. , Tanoue, A. , & Tsujimoto, G. (2007). Clinical implications from studies of alpha1 adrenergic receptor knockout mice. Biochemical Pharmacology, 73(8), 1107–1112. 10.1016/j.bcp.2006.11.002 [DOI] [PubMed] [Google Scholar]
  86. Kountz, T. S. , Lee, K. S. , Aggarwal‐Howarth, S. , Curran, E. , Park, J. M. , Harris, D. A. , … Hague, C. (2016). Endogenous N‐terminal domain cleavage modulates α1D‐adrenergic receptor pharmacodynamics. The Journal of Biological Chemistry, 291(35), 18210–18221. 10.1074/jbc.M116.729517 [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Lachnit, W. G. , Tran, A. M. , Clarke, D. E. , & Ford, A. P. (1997). Pharmacological characterization of an alpha 1A‐adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat. British Journal of Pharmacology, 120(5), 819–826. 10.1038/sj.bjp.0700983 [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Langer, S. Z. (1974). Presynaptic regulation of catecholamine release. Biochemical Pharmacology, 23(13), 1793–1800. [DOI] [PubMed] [Google Scholar]
  89. Langer, S. Z. (1999). History and nomenclature of alpha1‐adrenoceptors. European Urology, 36(Suppl 1), 2–6. [DOI] [PubMed] [Google Scholar]
  90. Lattion, A. L. , Diviani, D. , & Cotecchia, S. (1994). Truncation of the receptor carboxyl terminus impairs agonist‐dependent phosphorylation and desensitization of the alpha 1B‐adrenergic receptor. The Journal of Biological Chemistry, 269(36), 22887–22893. [PubMed] [Google Scholar]
  91. Leeb‐Lundberg, L. M. , Cotecchia, S. , Lomasney, J. W. , DeBernardis, J. F. , Lefkowitz, R. J. , & Caron, M. G. (1985). Phorbol esters promote alpha 1‐adrenergic receptor phosphorylation and receptor uncoupling from inositol phospholipid metabolism. Proceedings of the National Academy of Sciences of the United States of America, 82(17), 5651–5655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Lyssand, J. S. , Defino, M. C. , Tang, X. B. , Hertz, A. L. , Feller, D. B. , Wacker, J. L. , … Hague, C. (2008). Blood pressure is regulated by an {alpha}1D‐adrenergic receptor/dystrophin signalosome. The Journal of Biological Chemistry, 283(27), 18792–18800. 10.1074/jbc.M801860200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Mallard, N. J. , Marshall, R. W. , Sithers, A. J. , & Spriggs, T. L. (1992). Separation of putative alpha 1A‐ and alpha 1B‐adrenoceptor mediated components in the tension response of the rat vas deferens to electrical field stimulation. British Journal of Pharmacology, 105(3), 727–731. 10.1111/j.1476-5381.1992.tb09046.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Marti, D. , Miquel, R. , Ziani, K. , Gisbert, R. , Ivorra, M. D. , Anselmi, E. , … D'Ocon, P. (2005). Correlation between mRNA levels and functional role of alpha1‐adrenoceptor subtypes in arteries: Evidence of alpha1L as a functional isoform of the alpha1A‐adrenoceptor. American journal of physiology. Heart and Circulatory Physiology, 289(5), H1923–H1932. 10.1152/ajpheart.00288.2005 [DOI] [PubMed] [Google Scholar]
  95. McGrath, J. C. (2015). Localization of α‐adrenoceptors: JR Vane Medal Lecture. British Journal of Pharmacology, 172(5), 1179–1194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. McVary, K. T. , Roehrborn, C. G. , Avins, A. L. , Barry, M. J. , Bruskewitz, R. C. , Donnell, R. F. , … Wei, J. T. (2011). Update on AUA guideline on the management of benign prostatic hyperplasia. The Journal of Urology, 185(5), 1793–1803. 10.1016/j.juro.2011.01.074 [DOI] [PubMed] [Google Scholar]
  97. Mendes, F. R. , Hamamura, M. , Queiroz, D. B. , Porto, C. S. , & Avellar, M. C. (2004). Effects of androgen manipulation on alpha1‐adrenoceptor subtypes in the rat seminal vesicle. Life Sciences, 75(12), 1449–1463. 10.1016/j.lfs.2004.03.011 [DOI] [PubMed] [Google Scholar]
  98. Methven, L. , McBride, M. , Wallace, G. A. , & McGrath, J. C. (2009). The alpha 1B/D‐adrenoceptor knockout mouse permits isolation of the vascular alpha 1A‐adrenoceptor and elucidates its relationship to the other subtypes. British Journal of Pharmacology, 158(1), 209–224. 10.1111/j.1476-5381.2009.00269.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Methven, L. , Simpson, P. C. , & McGrath, J. C. (2009). Alpha1A/B‐knockout mice explain the native alpha1D‐adrenoceptor's role in vasoconstriction and show that its location is independent of the other alpha1‐subtypes. British Journal of Pharmacology, 158(7), 1663–1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Michel, M. C. , & Vrydag, W. (2006). Alpha1‐, alpha2‐ and beta‐adrenoceptors in the urinary bladder, urethra and prostate. British Journal of Pharmacology, 147(Suppl 2), S88–S119. 10.1038/sj.bjp.0706619 [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Michelotti, G. A. , Price, D. T. , & Schwinn, D. A. (2000). Alpha 1‐adrenergic receptor regulation: Basic science and clinical implications. Pharmacology & Therapeutics, 88(3), 281–309. 10.1016/S0163-7258(00)00092-9 [DOI] [PubMed] [Google Scholar]
  102. Minneman, K. P. , Theroux, T. L. , Hollinger, S. , Han, C. , & Esbenshade, T. A. (1994). Selectivity of agonists for cloned alpha 1‐adrenergic receptor subtypes. Molecular Pharmacology, 46(5), 929–936. [PubMed] [Google Scholar]
  103. Mota, P. M. , & Norris, J. H. (2016). Review on surgical management of ptosis and the use of phenylephrine: A national survey of British Oculoplastic Surgery Society (BOPSS) UK Consultants. Orbit, 35(6), 339–342. 10.1080/01676830.2016.1193547 [DOI] [PubMed] [Google Scholar]
  104. Myagmar, B. E. , Flynn, J. M. , Cowley, P. M. , Swigart, P. M. , Montgomery, M. D. , Thai, K. , … Simpson, P. C. (2017). Adrenergic receptors in individual ventricular myocytes: The beta‐1 and alpha‐1B are in all cells, the alpha‐1A is in a subpopulation, and the beta‐2 and beta‐3 are mostly absent. Circulation Research, 120(7), 1103–1115. 10.1161/CIRCRESAHA.117.310520 [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Nascimento‐Viana, J. B. , Carvalho, A. R. , Nasciutti, L. E. , Alcántara‐Hernández, R. , Chagas‐Silva, F. , Souza, P. A. , … Silva, C. L. (2016). New multi‐target antagonists of α1A‐, α1D‐adrenoceptors and 5‐HT1A receptors reduce human hyperplastic prostate cell growth and the increase of intraurethral pressure. The Journal of Pharmacology and Experimental Therapeutics, 356(1), 212–222. 10.1124/jpet.115.227066 [DOI] [PubMed] [Google Scholar]
  106. Noguera, M. A. , Ivorra, M. D. , & D'Ocon, P. (1996). Functional evidence of inverse agonism in vascular smooth muscle. British Journal of Pharmacology, 119(1), 158–164. 10.1111/j.1476-5381.1996.tb15689.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Nourian, Z. , Mow, T. , Muftic, D. , Burek, S. , Pedersen, M. L. , Matz, J. , … Mulvany, M. J. (2008). Orthostatic hypotensive effect of antipsychotic drugs in Wistar rats by in vivo and in vitro studies of alpha1‐adrenoceptor function. Psychopharmacology, 199(1), 15–27. 10.1007/s00213-007-1064-9 [DOI] [PubMed] [Google Scholar]
  108. O'Connell, T. D. , Jensen, B. C. , Baker, A. J. , & Simpson, P. C. (2014). Cardiac alpha1‐adrenergic receptors: Novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacological Reviews, 66(1), 308–333. 10.1124/pr.112.007203 [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Oelke, M. , Bachmann, A. , Descazeaud, A. , Emberton, M. , Gravas, S. , Michel, M. C. , … European Association of Urology (2013). EAU guidelines on the treatment and follow‐up of non‐neurogenic male lower urinary tract symptoms including benign prostatic obstruction. European Urology, 64(1), 118–140. 10.1016/j.eururo.2013.03.004 [DOI] [PubMed] [Google Scholar]
  110. Pacini, E. S. A. , Castilho, A. C. S. , Hebeler‐Barbosa, F. , Pupo, A. S. , & Kiguti, L. R. A. (2018). Contraction of rat cauda epididymis smooth muscle to α1‐adrenoceptor activation is mediated by α1A‐adrenoceptors. The Journal of Pharmacology and Experimental Therapeutics, 366(1), 21–28. [DOI] [PubMed] [Google Scholar]
  111. Perez, D. M. , & Doze, V. A. (2011). Cardiac and neuroprotection regulated by α(1)‐adrenergic receptor subtypes. Journal of Receptor and Signal Transduction Research, 31(2), 98–110. 10.3109/10799893.2010.550008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Perez‐Aso, M. , Segura, V. , Monto, F. , Barettino, D. , Noguera, M. A. , Milligan, G. , & D'Ocon, P. (2013). The three α1‐adrenoceptor subtypes show different spatio‐temporal mechanisms of internalization and ERK1/2 phosphorylation. Biochimica et Biophysica Acta, 1833(10), 2322–2333. 10.1016/j.bbamcr.2013.06.013 [DOI] [PubMed] [Google Scholar]
  113. Philipp, M. , & Hein, L. (2004). Adrenergic receptor knockout mice: Distinct functions of 9 receptor subtypes. Pharmacology & Therapeutics, 101(1), 65–74. 10.1016/j.pharmthera.2003.10.004 [DOI] [PubMed] [Google Scholar]
  114. Piascik, M. T. , Guarino, R. D. , Smith, M. S. , Soltis, E. E. , Saussy, D. L. Jr. , & Perez, D. M. (1995). The specific contribution of the novel alpha‐1D adrenoceptor to the contraction of vascular smooth muscle. The Journal of Pharmacology and Experimental Therapeutics, 275(3), 1583–1589. [PubMed] [Google Scholar]
  115. Price, D. T. , Schwinn, D. A. , Lomasney, J. W. , Allen, L. F. , Caron, M. G. , & Lefkowitz, R. J. (1993). Identification, quantification, and localization of mRNA for three distinct alpha 1 adrenergic receptor subtypes in human prostate. The Journal of Urology, 150(2 Pt 1), 546–551. 10.1016/S0022-5347(17)35544-1 [DOI] [PubMed] [Google Scholar]
  116. Price, R. R. , Morris, D. P. , Biswas, G. , Smith, M. P. , & Schwinn, D. A. (2002). Acute agonist‐mediated desensitization of the human alpha 1a‐adrenergic receptor is primarily independent of carboxyl terminus regulation: implications for regulation of alpha 1aAR splice variants. The Journal of Biological Chemistry, 277(11), 9570–9579. [DOI] [PubMed] [Google Scholar]
  117. Prihandoko, R. , Alvarez‐Curto, E. , Hudson, B. D. , Butcher, A. J. , Ulven, T. , Miller, A. M. , … Milligan, G. (2016). Distinct phosphorylation clusters determine the signaling outcome of free fatty acid receptor 4/G protein‐coupled receptor 120. Molecular Pharmacology, 89(5), 505–520. 10.1124/mol.115.101949 [DOI] [PubMed] [Google Scholar]
  118. Pupo, A. S. (1998). Functional effects of castration on alpha1‐adrenoceptors in rat vas deferens. European Journal of Pharmacology, 351(2), 217–223. 10.1016/S0014-2999(98)00315-X [DOI] [PubMed] [Google Scholar]
  119. Pupo, A. S. , Duarte, D. A. , Lima, V. , Teixeira, L. B. , Parreiras, E. S. L. T. , & Costa‐Neto, C. M. (2016). Recent updates on GPCR biased agonism. Pharmacological Research, 112, 49–57. [DOI] [PubMed] [Google Scholar]
  120. Pupo, A. S. , Uberti, M. A. , & Minneman, K. P. (2003). N‐terminal truncation of human alpha1D‐adrenoceptors increases expression of binding sites but not protein. European Journal of Pharmacology, 462(1–3), 1–8. [DOI] [PubMed] [Google Scholar]
  121. Queiroz, D. B. , Mendes, F. R. , Porto, C. S. , & Avellar, M. C. (2002). Alpha1‐adrenoceptor subtypes in rat epididymis and the effects of sexual maturation. Biology of Reproduction, 66(2), 508–515. 10.1095/biolreprod66.2.508 [DOI] [PubMed] [Google Scholar]
  122. Rodríguez‐Pérez, C. E. , Romero‐Ávila, M. T. , Reyes‐Cruz, G. , & García‐Sáinz, J. A. (2009). Signaling properties of human alpha(1D)‐adrenoceptors lacking the carboxyl terminus: Intrinsic activity, agonist‐mediated activation, and desensitization. Naunyn‐Schmiedeberg's Archives of Pharmacology, 380(2), 99–107. [DOI] [PubMed] [Google Scholar]
  123. Roepke, S. , Danker‐Hopfe, H. , Repantis, D. , Behnia, B. , Bernard, F. , Hansen, M. L. , & Otte, C. (2017). Doxazosin, an α‐1‐adrenergic‐receptor antagonist, for nightmares in patients with posttraumatic stress disorder and/or borderline personality disorder: A chart review. Pharmacopsychiatry, 50(1), 26–31. 10.1055/s-0042-107794 [DOI] [PubMed] [Google Scholar]
  124. Rudner, X. L. , Berkowitz, D. E. , Booth, J. V. , Funk, B. L. , Cozart, K. L. , D'Amico, E. B. , … Schwinn, D. A. (1999). Subtype specific regulation of human vascular alpha(1)‐adrenergic receptors by vessel bed and age. Circulation, 100(23), 2336–2343. [DOI] [PubMed] [Google Scholar]
  125. Sanbe, A. , Tanaka, Y. , Fujiwara, Y. , Tsumura, H. , Yamauchi, J. , Cotecchia, S. , … Tanoue, A. (2007). Alpha1‐adrenoceptors are required for normal male sexual function. British Journal of Pharmacology, 152(3), 332–340. 10.1038/sj.bjp.0707366 [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Schwartz, S. L. , Cao, C. , Pylypenko, O. , Rak, A. , & Wandinger‐Ness, A. (2007). Rab GTPases at a glance. Journal of Cell Science, 120(Pt 22), 3905–3910. 10.1242/jcs.015909 [DOI] [PubMed] [Google Scholar]
  127. Segura, V. , Perez‐Aso, M. , Monto, F. , Carceller, E. , Noguera, M. A. , Pediani, J. , … D'Ocon, P. (2013). Differences in the signaling pathways of alpha(1A)‐ and alpha(1B)‐adrenoceptors are related to different endosomal targeting. PLoS ONE, 8(5), e64996 10.1371/journal.pone.0064996 [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Sharman, J. L. , Harding, S. D. , Southan, C. , Faccenda, E. , Pawson, A. J. , Davies, J. A. , & NC‐IUPHAR. (2018). Accessing expert‐curated pharmacological data in the IUPHAR/BPS guide to PHARMACOLOGY. Current Protocols in Bioinformatics, 61(1), 1.34.1–1.34.46. 10.1002/cpbi.46 [DOI] [PubMed] [Google Scholar]
  129. Sigala, S. , Dellabella, M. , Milanese, G. , Fornari, S. , Faccoli, S. , Palazzolo, F. , … Muzzonigro, G. (2005). Evidence for the presence of alpha1 adrenoceptor subtypes in the human ureter. Neurourology and Urodynamics, 24(2), 142–148. [DOI] [PubMed] [Google Scholar]
  130. da Silva Junior, E. D. , Sato, M. , Merlin, J. , Broxton, N. , Hutchinson, D. S. , Ventura, S. , … Summers, R. J. (2017). Factors influencing biased agonism in recombinant cells expressing the human alpha1A‐adrenoceptor. British Journal of Pharmacology, 174(14), 2318–2333. 10.1111/bph.13837 [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Silva, M. A. , Megale, A. , Avellar, M. C. , & Porto, C. S. (1999). Expression and pharmacological characterization of alpha1‐adrenoceptors in rat seminal vesicle. European Journal of Pharmacology, 381(2–3), 141–149. [DOI] [PubMed] [Google Scholar]
  132. Stanasila, L. , Abuin, L. , Dey, J. , & Cotecchia, S. (2008). Different internalization properties of the alpha1a‐ and alpha1b‐adrenergic receptor subtypes: The potential role of receptor interaction with beta‐arrestins and AP50. Molecular Pharmacology, 74(3), 562–573. 10.1124/mol.107.043422 [DOI] [PubMed] [Google Scholar]
  133. Starke, K. , Montel, H. , Gayk, W. , & Merker, R. (1974). Comparison of the effects of clonidine on pre‐ and postsynaptic adrenoceptors in the rabbit pulmonary artery. Alpha‐sympathomimetic inhibition of Neurogenic vasoconstriction. Naunyn‐Schmiedeberg's Archives of Pharmacology, 285(2), 133–150. 10.1007/BF00501149 [DOI] [PubMed] [Google Scholar]
  134. Stassen, F. R. , Maas, R. G. , Schiffers, P. M. , Janssen, G. M. , & De Mey, J. G. (1998). A positive and reversible relationship between adrenergic nerves and alpha‐1A adrenoceptors in rat arteries. The Journal of Pharmacology and Experimental Therapeutics, 284(1), 399–405. [PubMed] [Google Scholar]
  135. Stenmark, H. (2009). Rab GTPases as coordinators of vesicle traffic. Nature Reviews. Molecular Cell Biology, 10(8), 513–525. 10.1038/nrm2728 [DOI] [PubMed] [Google Scholar]
  136. Stone, E. A. , Cotecchia, S. , Lin, Y. , & Quartermain, D. (2002). Role of brain alpha 1B‐adrenoceptors in modafinil‐induced behavioral activity. Synapse, 46(4), 269–270. [DOI] [PubMed] [Google Scholar]
  137. Stone, E. A. , Lin, Y. , Rosengarten, H. , Kramer, H. K. , & Quartermain, D. (2003). Emerging evidence for a central epinephrine‐innervated alpha 1‐adrenergic system that regulates behavioral activation and is impaired in depression. Neuropsychopharmacology, 28(8), 1387–1399. 10.1038/sj.npp.1300222 [DOI] [PubMed] [Google Scholar]
  138. Taki, N. , Tanaka, T. , Zhang, L. , Suzuki, F. , Israilova, M. , Taniguchi, T. , … Muramatsu, I. (2004). Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery. British Journal of Pharmacology, 142(4), 647–656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  139. Tanoue, A. , Koshimizu, T. A. , Shibata, K. , Nasa, Y. , Takeo, S. , & Tsujimoto, G. (2003). Insights into alpha1 adrenoceptor function in health and disease from transgenic animal studies. Trends in Endocrinology and Metabolism: TEM, 14(3), 107–113. 10.1016/S1043-2760(03)00026-2 [DOI] [PubMed] [Google Scholar]
  140. Tanoue, A. , Koshimizu, T. A. , & Tsujimoto, G. (2002). Transgenic studies of alpha(1)‐adrenergic receptor subtype function. Life Sciences, 71(19), 2207–2215. [DOI] [PubMed] [Google Scholar]
  141. Tobin, A. B. (2008). G‐protein‐coupled receptor phosphorylation: Where, when and by whom. British Journal of Pharmacology, 153(Suppl 1), S167–S176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  142. Tobin, A. B. , Butcher, A. J. , & Kong, K. C. (2008). Location, location, location…site‐specific GPCR phosphorylation offers a mechanism for cell‐type‐specific signalling. Trends in Pharmacological Sciences, 29(8), 413–420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Toews, M. L. , Prinster, S. C. , & Schulte, N. A. (2003). Regulation of alpha‐1B adrenergic receptor localization, trafficking, function, and stability. Life Sciences, 74(2–3), 379–389. [DOI] [PubMed] [Google Scholar]
  144. Vaidyanathan, S. , Williamson, P. , Clearie, K. , Khan, F. , & Lipworth, B. (2010). Fluticasone reverses oxymetazoline‐induced tachyphylaxis of response and rebound congestion. American Journal of Respiratory and Critical Care Medicine, 182(1), 19–24. [DOI] [PubMed] [Google Scholar]
  145. Vail, E. , Gershengorn, H. B. , Hua, M. , Walkey, A. J. , Rubenfeld, G. , & Wunsch, H. (2017). Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA: The Journal of the American Medical Association, 317(14), 1433–1442. 10.1001/jama.2017.2841 [DOI] [PubMed] [Google Scholar]
  146. Vázquez‐Prado, J. , Casas‐González, P. , & García‐Sáinz, J. A. (2003). G protein‐coupled receptor cross‐talk: Pivotal roles of protein phosphorylation and protein–protein interactions. Cellular Signalling, 15(6), 549–557. [DOI] [PubMed] [Google Scholar]
  147. Vazquez‐Prado, J. , & Garcia‐Sainz, J. A. (1996). Effect of phorbol myristate acetate on alpha 1‐adrenergic action in cells expressing recombinant alpha 1‐adrenoceptor subtypes. Molecular Pharmacology, 50(1), 17–22. [PubMed] [Google Scholar]
  148. Vazquez‐Prado, J. , Medina, L. C. , Romero‐Avila, M. T. , Gonzalez‐Espinosa, C. , & Garcia‐Sainz, J. A. (2000). Norepinephrine‐ and phorbol ester‐induced phosphorylation of alpha(1a)‐adrenergic receptors. Functional aspects. The Journal of Biological Chemistry, 275(9), 6553–6559. [DOI] [PubMed] [Google Scholar]
  149. Villalobos‐Molina, R. , & Ibarra, M. (1999). Vascular alpha 1D‐adrenoceptors: Are they related to hypertension? Archives of Medical Research, 30(5), 347–352. 10.1016/S0188-0128(99)00047-0 [DOI] [PubMed] [Google Scholar]
  150. Villalobos‐Molina, R. , & Ibarra, M. (2005). Increased expression and function of vascular alpha1D‐adrenoceptors may mediate the prohypertensive effects of angiotensin II. Molecular Interventions, 5(6), 340–342. [DOI] [PubMed] [Google Scholar]
  151. Villalobos‐Molina, R. , López‐Guerrero, J. J. , & Ibarra, M. (1999). Functional evidence of alpha1D‐adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats. British Journal of Pharmacology, 126(7), 1534–1536. 10.1038/sj.bjp.0702468 [DOI] [PMC free article] [PubMed] [Google Scholar]
  152. Villalobos‐Molina, R. , Vazquez‐Cuevas, F. G. , Lopez‐Guerrero, J. J. , Figueroa‐Garcia, M. C. , Gallardo‐Ortiz, I. A. , Ibarra, M. , … Elizondo, G. (2008). Vascular alpha‐1D‐adrenoceptors are overexpressed in aorta of the aryl hydrocarbon receptor null mouse: Role of increased angiotensin II. Autonomic & Autacoid Pharmacology, 28(2–3), 61–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Wang, G. , Wei, Z. , & Wu, G. (2018). Role of Rab GTPases in the export trafficking of G protein‐coupled receptors. Small GTPases, 9(1–2), 130–135. 10.1080/21541248.2016.1277000 [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Wang, G. , & Wu, G. (2012). Small GTPase regulation of GPCR anterograde trafficking. Trends in Pharmacological Sciences, 33(1), 28–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Wang, S. Y. , Song, Y. , Xu, M. , He, Q. H. , Han, Q. D. , & Zhang, Y. Y. (2007). Internalization and distribution of three alpha1‐adrenoceptor subtypes in HEK293A cells before and after agonist stimulation. Acta Pharmacologica Sinica, 28(3), 359–366. [DOI] [PubMed] [Google Scholar]
  156. White, C. W. , Choong, Y. T. , Short, J. L. , Exintaris, B. , Malone, D. T. , Allen, A. M. , … Ventura, S. (2013). Male contraception via simultaneous knockout of alpha1A‐adrenoceptors and P2X1‐purinoceptors in mice. Proceedings of the National Academy of Sciences of the United States of America, 110(51), 20825–20830. 10.1073/pnas.1318624110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Woodcock, E. A. , Du, X. J. , Reichelt, M. E. , & Graham, R. M. (2008). Cardiac alpha 1‐adrenergic drive in pathological remodelling. Cardiovascular Research, 77(3), 452–462. [DOI] [PubMed] [Google Scholar]
  158. Wu, S. C. , & O'Connell, T. D. (2015). Nuclear compartmentalization of alpha1‐adrenergic receptor signaling in adult cardiac myocytes. Journal of Cardiovascular Pharmacology, 65(2), 91–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  159. Xin, X. , Yang, N. , Eckhart, A. D. , & Faber, J. E. (1997). Alpha1D‐adrenergic receptors and mitogen‐activated protein kinase mediate increased protein synthesis by arterial smooth muscle. Molecular Pharmacology, 51(5), 764–775. 10.1124/mol.51.5.764 [DOI] [PubMed] [Google Scholar]
  160. Yono, M. , Tanaka, T. , Tsuji, S. , Hori, M. , Irie, S. , Sakata, Y. , … Latifpour, J. (2012). A comparison of the expression and contractile function of alpha1‐adrenoceptors in seminal vesicle and vas deferens from normotensive and hypertensive rats. European Journal of Pharmacology, 694(1–3), 104–110. 10.1016/j.ejphar.2012.08.005 [DOI] [PubMed] [Google Scholar]
  161. Zerial, M. , & McBride, H. (2001). Rab proteins as membrane organizers. Nature Reviews. Molecular Cell Biology, 2(2), 107–117. [DOI] [PubMed] [Google Scholar]
  162. Ziani, K. , Gisbert, R. , Noguera, M. A. , Ivorra, M. D. , & D'Ocon, P. (2002). Modulatory role of a constitutively active population of alpha(1D)‐adrenoceptors in conductance arteries. American Journal of Physiology. Heart and Circulatory Physiology, 282(2), H475–H481. [DOI] [PubMed] [Google Scholar]
  163. Zindel, D. , Engel, S. , Bottrill, A. R. , Pin, J. P. , Prezeau, L. , Tobin, A. B. , … Butcher, A. J. (2016). Identification of key phosphorylation sites in PTH1R that determine arrestin3 binding and fine‐tune receptor signaling. The Biochemical Journal, 473(22), 4173–4192. 10.1042/BCJ20160740 [DOI] [PMC free article] [PubMed] [Google Scholar]
  164. Zuscik, M. J. , Sands, S. , Ross, S. A. , Waugh, D. J. , Gaivin, R. J. , Morilak, D. , & Perez, D. M. (2000). Overexpression of the alpha1B‐adrenergic receptor causes apoptotic neurodegeneration: Multiple system atrophy. Nature Medicine, 6(12), 1388–1394. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES