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. 2024 Oct 31;10(5):274–282. doi: 10.52601/bpr.2024.240906

β-adrenergic regulation of Ca2+ signaling in heart cells

Bo Yang 1, Shi-Qiang Wang 2, Hua-Qian Yang 1,*
PMCID: PMC11554573  PMID: 39539286

Abstract

β-adrenergic receptors (βARs) play significant roles in regulating Ca2+ signaling in cardiac myocytes, thus holding a key function in modulating heart performance. βARs regulate the influx of extracellular Ca2+ and the release and uptake of Ca2+ from the sarcoplasmic reticulum (SR) by activating key components such as L-type calcium channels (LTCCs), ryanodine receptors (RyRs) and phospholamban (PLN), mediated by the phosphorylation actions by protein kinase A (PKA). In cardiac myocytes, the presence of β2AR provides a protective mechanism against potential overstimulation of β1AR, which may aid in the restoration of cardiac dysfunctions. Understanding the Ca2+ regulatory signaling pathways of βARs in cardiac myocytes and the differences among various βAR subtypes are crucial in cardiology and hold great potential for developing treatments for heart diseases.

Keywords: β-adrenergic receptor (βAR), Ca2+ signaling, Cardiac myocytes, Compartmentalization

INTRODUCTION

β-adrenergic receptors (βARs) belong to the G protein-coupled receptor (GPCR) superfamily, and are essential for regulating the function of the cardiovascular system. βARs are activated by catecholamines released from sympathetic nerve terminals and adrenal medulla under stress conditions, which increase heart rate and blood pumping capability of the heart (Bers 2002). The positive chronotropic, dromotropic and inotropic effects ensure the energy supply of emergent needs.

Currently, there are three identified subtypes of βARs (β1AR, β2AR, β3AR), while the existence of a fourth subtype (β4AR) is still a subject of debate (Gauthier et al. 1996). These three isoforms exhibit different affinities for different ligands, rendering the selectivity of isoform activation (Bristow et al. 1986). The ratio of β1AR/β2AR expression in the healthy human heart is approximately 4:1, while the expression of β3AR is minimal. Both β1AR and β2AR respond to catecholamine stimulation and mediate positive inotropic effects in heart cells. β1AR plays a dominant role in increasing chronotropy and inotropy in cardiac myocytes, whereas β2AR produces only modest chronotropic effects (Xiang and Kobilka 2003; Xiao et al. 2006).

Epinephrine and norepinephrine are native catecholamine ligands of βARs (Bunemann et al. 1999; Hain et al. 1995; Nikolaev et al. 2006; Nikolaev et al. 2010). With catecholamine binding, βARs undergo conformational changes that enable its coupling to heterotrimeric G proteins, resulting in the substitution of the GDP on the Gα subunit of G-proteins by GTP and subsequent dissociation of Gβγ subunits (Wess 1997). Gα-GTP then stimulates adenylyl cyclase (AC) to catalyze the formation of cyclic AMP (cAMP). cAMP regulates a wide variety of cellular processes through activating a variety of downstream signaling molecules, including protein kinase A (PKA). PKA phosphorylates L-type Ca2+ channels (LTCCs) in the cell membrane or T-tubules, ryanodine receptor (RyR) Ca2+ release channels and phospholamban (PLN) in the sarcoplasmic reticulum (SR), and thereby up-regulates LTCC Ca2+ influx, SR Ca2+ release and cytosolic Ca2+ uptake (Fig. 1).

Figure 1.

Figure 1

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Illustration of β-adrenergic regulation of Ca2+ signaling in heart cells

REGULATION OF LTCC

LTCCs are the predominant mediator of Ca2+ influx in the cardiomyocytes playing an initiation role in the excitation-contraction coupling. In general, LTCCs are composed of α1, α2, β, δ and γ subunits. α1 is the pore-forming subunit with voltage sensors. α2/δ and β subunits modulate the expression, voltage dependence and gating kinetics of the channel (Bodi et al. 2005).

Several PKA phosphorylation sites in the α1 subunit have been identified (Fu et al. 2014; Hulme et al. 2006; Yang et al. 2016). βAR agonists, such as isoproterenol, increase the phosphorylation level of S1928 in the distal C-terminal domain (Hulme et al. 2006), which can be blocked by βAR antagonists. Interestingly, LTCCs with S1928 mutated to alanine still retain 70%–80% response to βAR stimulation, indicating that S1928 is not the major phosphorylation site for βAR stimulation (Benitah et al. 2010; Ganesan et al. 2006; Hulme et al. 2003, 2006). S1700 and T1704 located at the interface between the proximal and distal C-terminal domain are also phosphorylated in βAR regulation of LTCCs (Fu et al. 2013, 2014). Again, mutations of both S1700 and T1704 cannot eliminate βAR effects (Fu et al. 2013).

The regulatory β2 subunit plays a crucial role in LTCCs regulation in response to βAR stimulation (Haase et al. 1993). S478 and S479 were identified as the phosphorylation sites of PKA in β2 subunit (Gerhardstein et al. 1999). Mutating S478 and S479 to alanine in the β2 subunit inhibits PKA-mediated Ca2+ current increase in transfected cells (Bunemann et al. 1999). This result suggests that phosphorylation of S478 or S479 contributes to PKA-mediated regulation of LTCCs.

Monomeric G proteins, such as Rem and Rad, function as endogenous LTCC inhibitors (Beguin et al. 2001; Finlin et al. 2003). Recent analysis from a proximity proteomics screen provided solid evidence that Rad is enriched in the LTCC microenvironment but is depleted during β-adrenergic stimulation. Phosphorylation by PKA decreases Rad affinity for β subunits and increases LTCC open probability (Liu et al. 2020). Four serines in Rad have been identified as PKA phosphorylation sites, and mutation of these four serines or disrupting the interaction between LTCC β subunit and Rad reduced heart rate and basal contractility, and greatly diminished β-adrenergic contractile response (Papa et al. 2022, 2024).

A kinase anchoring protein 15 (AKAP15) is a lipid-anchored protein with a single amphipathic helix that binds PKA. AKAP15 colocalizes and associates with LTCC in T-tubules (Gray et al. 1998). PKA tethered to a leucine zipper motif in the C-terminal domain of the LTCC α1 subunit via AKAP15 (Hulme et al. 2002), which is essential for β-adrenergic regulation of LTCC (Hulme et al. 2003).

LTCCs are also phosphorylated by Ca2+/calmodulin-dependent kinase II (CaMKII). CaMKII is activated by βAR stimulation via guanine nucleotide exchange protein directly activated by cAMP (Epac) (Curran et al. 2007; Grimm and Brown 2010). Mutations at sites S1512 and S1570 of α1 subunit (Hudmon et al. 2005) and T498 of β2 subunit (Koval et al. 2010) reduce Ca2+ influx.

Besides, cardiac phosphatase activities also play important roles in the regulation of Ca2+ homeostasis. Phosphatase type 1 (PP1) and 2A (PP2A) are the major isotypes of cardiac phosphatases, comprising over 90% of the protein phosphatases in cardiomyocytes (Lüss et al. 2000). PP1 is reported to contribute to the dephosphorylation of LTCC, RyR, and PLB. Whereas, PP2A is mainly involved in the dephosphorylation of myofibrillar proteins, including troponin I and myosin-binding protein C (Metzger and Westfall 2004).

In recent years, a few proteins have been reported to modify the β-adrenergic regulation of LTCCs. Sphingosine-1-phosphate (S1P), a circulating bioactive sphingolipid, has been implicated in the regulation of several cellular processes including cardiac Ca2+ handling (Means and Brown 2009). S1P does not affect the basal LTCC current, but partially reverses the regulation of βAR activation on LTCCs through a signaling pathway involving the interaction between P21-activated kinase 1 (Pak1) and protein phosphatase 2A (PP2A) (Egom et al. 2016). Ahnak functions as a suppressor of LTCCs by sequestering the β2 subunit through a strong binding to the LTCC β2 subunit (Hohaus et al. 2002). Rem GTPase interacts with LTCC β2 subunit and inhibits LTCC currents. The inhibitor effects can be rescued by LTCC activators such as BayK8644, but not by the βAR stimulation (Xu et al. 2010). Besides the functional coupling regulators, there were some structural coupling factors, such as Bridging Integrator 1 (BIN1) and caveolin-3. BIN1 is essential for the localization of LTCCs to T-tubules in cardiomyocytes and affects LTCC regulation by βAR stimulation (Kumari et al. 2018). In heart cells, a subpopulation of LTCCs localizes in caveolae. Caveolae are specialized membrane microdomains and are supported by the structural protein caveolin-3. It is well known that β2AR is enriched in caveolae. There is evidence showing that regulation of LTCCs by β2AR, but not β1AR, is eliminated when caveolae were disrupted (Balijepalli et al. 2006). This indicates that LTCCs are coupled to β1AR signaling outside of caveolae.

REGULATION OF RyRs

RyRs are major Ca2+ release channels in the SR of striated myocytes or endoplasmic reticulum (ER) of other cells. RyRs bind to ryanodine in their open state. Early studies using radiolabeled ryanodine have shown that phosphorylation of RyR2 by PKA increased channel activity (Takasago et al. 1991). However, the identification of the phosphorylation site critical for βAR response has been highly controversial. It has been proposed that the phosphorylation of S2808 by PKA sensitizes the response of RyRs to cytosolic Ca2+ change (Wehrens et al. 2004a). However, the mouse model harboring the S2808A mutation has normal inotropic and chronotropic responses to βAR stimulation (MacDonnell et al. 2008). S2808A cardiomyocytes exhibit blunted enhancement of systolic Ca2+ transients at 3 Hz but not at lower frequencies (Benkusky et al. 2007). There is also evidence that the phosphorylation of S2030 by PKA enhances RyR2 responsiveness to luminal Ca2+ (Xiao et al. 2005, 2007). However, data from different labs questioned Ser2030 as a physiological PKA phosphorylation site (Huke and Bers 2008; Wehrens et al. 2006).

Besides PKA-mediated phosphorylation, βAR-activated CaMKII specifically phosphorylates S2815 in RyRs (Kushnir et al. 2010; Wehrens et al. 2004b). Phosphorylation at S2815 increases the open probability of RyR2 by sensitizing the channel (Wehrens et al. 2004b). While cardiac-specific CaMKII overexpression enhances SR Ca2+ fractional release (Maier et al. 2003), cardiac-specific inhibition of CaMKII reduces isoproterenol-induced responses in SR Ca2+ release and heart rate (Wu et al. 2009).

In intact cells, βAR modulation of RyR function is difficult to measure, because βAR also increases LTCC Ca2+ current and SR Ca2+ loading. With a high-affinity Ca2+ indicator combined with a slow Ca2+ buffer agent EGTA to elicit Ca2+ spikes, it is demonstrated that isoproterenol synchronizes the Ca2+ release from RyR clusters (Song et al. 2001). When the SR Ca2+ load and Ca2+ current were controlled, isoproterenol stimulation of β1AR accelerates SR Ca2+ release kinetics without altering the amplitude of Ca2+ transients (Ginsburg and Bers 2004), agreeing well with the PKA-mediated synchronization of RyR Ca2+ release (Lakatta 2004; Wang and Wehrens 2010). However, experiments using UV photolysis to activate RyRs showed that isoproterenol enhances both the speed and the magnitude of Ca2+ transients in cells with controlled SR Ca2+ load (Ogrodnik and Niggli 2010). Using the loose-sealed patch clamp to trigger individual RyR Ca2+ release units, manifested as a Ca2+ spark, we observed that selective βAR stimulation enhances the amplitude of triggered sparks in an LTCC unitary current-independent manner. The Ca2+ release flux that underlies a Ca2+ spark is enhanced when the SR Ca2+ content is controlled to a comparable level. These results demonstrate unequivocally that the activation of RyRs is expedited and synchronized under βAR stimulation (Zhou et al. 2009).

REGULATION OF PLN

The rapid removal of Ca2+ from the cytoplasm is primarily facilitated by the sarco(endo)plasmic reticulum Ca2+ ATPase SERCA2a, which pumps Ca2+ back into the SR cavity and thus controls the amount of Ca2+ in the SR (Zhihao et al. 2020). PLB is the endogenous regulatory protein of SERCA2a activity and is the only regulatory protein of SERCA2a that is directly involved in the development of heart disease, including heart failure (Shanmugam et al. 2011; Weber et al. 2021).

There are two phosphorylation sites in PLN, Ser16 and Thr17, which are phosphorylated by PKA and CaMKII respectively (Kuschel et al. 1999; Simmerman et al. 1986; Xiao et al. 1994). Experiments with phosphorylation of PLN at either site increase SR Ca2+ load, and thus enhance SR Ca2+ release and accelerate cardiomyocyte relaxation (Li et al. 2002). Different from that of Ser16, the phosphorylation of Thr17 by β1AR is enhanced with increased frequency of electrical stimulation possibly because frequency-dependent accumulation of intracellular Ca2+ facilities CaMKII activation (Hagemann et al. 2000).

DIFFERENCE BETWEEN β1AR AND β2AR SIGNALING

The amino acid sequences of human β1AR and β2AR share only 71% identity in the transmembrane domains and 54% identity overall (Dixon et al. 1986). In the heart, β1AR-activated cAMP signaling increases the phosphorylation of sarcolemmal LTCCs and a multitude of intracellular regulatory proteins, including RyR, PLB and myofilaments (Xiao 2001). However, β2AR-mediated cAMP signaling specifically modulates LTCCs without affecting PLB and myofilaments in most mammalian species (Fig. 2) (Xiao and Lakatta 1993). Although in the human heart, β2AR stimulation increases PKA-dependent phosphorylation of intracellular regulatory proteins, its effects are much smaller than that induced by β1AR stimulation (Altschuld et al. 1995). Furthermore, β2ARs are expressed preferentially in the T-Tubule membrane, while β1ARs are distributed in both T-tubules and surface membrane (Nikolaev et al. 2010).

Figure 2.

Figure 2

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Illustration of compartmentalized β2AR-cAMP signaling in heart cells

βARs are G protein-coupled receptors. β1AR and β2AR both couple to Gs protein, while β2AR also couples to Gi protein (Fig. 2). Selective β2AR stimulation by zinterol does not enhance cardiomyocyte contraction in both wild-type (WT) mice and transgenic mice overexpressing human β2AR (TG4) (Zhou et al. 1999). After incubating cells with pertussis toxin (PTX), which abrogates Gi/Go function via ADP ribosylation, zinterol markedly increases contraction amplitude in both WT and TG4 cardiomyocytes, which can be completely abolished by the specific β2AR antagonist (Xiao et al. 1999). In cell-attached patch clamp experiment, β2AR agonist in bath solution outside the patch pipette cannot cause a discernible change in LTCC activity in the patch membrane, while local β2AR agonist in the pipette markedly increases the open probability of the patched channel. This sophisticated experiment indicates that β2AR signaling is confined in a highly localized microdomain. After PTX treatment, the channels in the patch membrane became responsive to agonist in the bath solution, suggesting that Gi plays an essential role in the compartmentalized β2AR signaling (Chen-Izu et al. 2000).

In addition to the impact of Gi protein, it is proposed that β2ARs reside in caveolae, which compartmentalize β2AR signaling. Indeed, caveolin-3 is of vital importance for the localization of β2AR and compartmentation of β2AR-cAMP signaling in healthy cardiomyocytes (Wright et al. 2014). Also, phosphodiesterase 4D (PDE4D) is recruited by β-arrestin2 to the vicinity of β2AR. Its hydrolysis of cAMP restricts the spatial diffusion of β2AR-activated cAMP signal (Fischmeister et al. 2006; Richter et al. 2008; Shi et al. 2017). Endogenous catecholamine ligands of βARs, epinephrine and norepinephrine, induced distinct β2AR signaling through G protein-coupled receptor kinase 2 (GRK2) phosphorylation and selective binding of Gs or Gi (Heubach et al. 2004; Wang et al. 2008), which further revealed the complexity of β2AR downstream signaling.

β2AR-MEDIATED OFFSIDE COMPARTMENTALIZATION OF β1AR SIGNALING

Accumulative evidence suggests that β1AR and β2AR pathways may have crosstalk. The activation of β2AR has been found to blunt the signaling of β1AR in failing heart cells (He et al. 2005). In transgenic mice overexpressing β2ARs, the contractility of cardiomyocytes is enhanced through spontaneous β2AR-cAMP signaling. However, these cells lose their ability to respond to β1AR stimulation (Zhang et al. 2000).

Recently, we have analyzed the interaction between β2AR and β1AR signaling. While isoproterenol normally up-regulates Ca2+ transients during cardiomyocyte excitation, salbutamol, a selective β2AR agonist, hinders the ability of isoproterenol to regulate Ca2+ transients (Yang et al. 2019). This effect can be eliminated either by rolipram, a PDE4 inhibitor, or by peptides that antagonize β-arrestin1. In the rat model harboring mutations of the phosphorylation sites in the C-terminus of β1AR, a putative binding domain for β-arrestin1 and GRK2, β2AR agonist no longer interferes with β1AR signaling. This study suggests that β2AR stimulation activates GRK2 to phosphorylate the C-terminus of β1AR, facilitates the recruitment of PDE4 to the phosphorylated β1AR, and compartmentalizes β1AR-cAMP signals within a sub-membrane nanodomain, preventing the PKA-dependent regulation of RyR and PLB. Because the compartmentalization of the β1AR pathway is rendered by the β2AR pathway in an offside manner, this signaling process is described as “offside compartmentalization” (Fig. 2) (Yang et al. 2019).

It is important to mention that the activation of offside compartmentalization can occur in vivo through the use of epinephrine, which hinders the regulation of heart contraction by norepinephrine (Yang et al. 2020). Epinephrine exhibits a limited preference for β2AR over β1AR as an adrenal hormone (Baker 2010), while norepinephrine predominantly stimulates β- and α1ARs as a sympathetic neurotransmitter (Minneman et al. 1981) and exhibits selectivity for β1AR over β2AR due to different entrance pathways to the extracellular binding pockets (Xu et al. 2021). Epinephrine and a less quantity of norepinephrine are tonically released from the adrenal glands (Paur et al. 2012). As prolonged activation of β1AR leads to cytotoxicity (Wu et al. 2017; Zhu et al. 2003), the offside compartmentalization initiated by β2AR signaling can serve as a negative feed-forward mechanism preventing the tonic β1AR activation by circulating catecholamines. Under the offside compartmentalization, βAR signaling is still able to synchronize SR Ca2+ release by up-regulating LTCC Ca2+ influx (Yang et al. 2020) and enhance the transient response of β1AR to norepinephrine during sympathetic excitation. Hence, in contrast to the robust and predictable E-C coupling regulation through overall β1AR signaling, the compartmentalized βAR regulation of E-C coupling, while being moderate, exhibits an "autoadaptive" nature in response to various physiological and pathological circumstances.

PATHOLOGICAL IMPLICATIONS

While βARs play essential roles in the physiological operation of Ca2+ signaling, their malfunction is implicated in a variety of pathological processes. Prolonged β1AR stimulation induces apoptosis in a CaMKII-dependent manner, and β2AR blockade exaggerates β1AR-induced apoptosis (Communal et al. 1999) possibly due to the absence of offside compartmentalization. In contrast, stimulation of β2AR protects cardiac myocytes against a wide range of apoptotic insults, including enhanced β1AR signaling, hypoxic treatment or induction of reactive oxygen species (ROS) (Zhu et al. 2001). Inhibition of β2AR-activated Gi–Gβγ–PI3K–PKB signaling eliminates these protective effects, and transforms β2AR signaling from anti-apoptotic to pro-apoptotic (Zhu et al. 2001; Chesley et al. 2000). Emerging evidence suggests that mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinases (ERK1 and ERK2) are also involved in β2AR-mediated anti-apoptotic signaling (Shizukuda and Buttrick 2002).

During the early-stage development of heart failure, the sympathetic nervous system adjusts its activity to increase cardiac output to compensate for the alterations of cardiac and peripheral hemodynamics (Toschi-Dias et al. 2017). However, the continuous hemodynamic stress promotes the chronic release of catecholamines. The elevated level of catecholamine (Bristow et al. 1982; Ungerer et al. 1993) leads to sustained and toxic β1AR-CaMKII signaling, which exacerbates the decline in cardiac function as observed in mid- and late-stages of heart failure (Brede et al. 2002; Johnson and Antoons 2018; Zhu et al. 2003).

CONCLUDING REMARKS

Heart disease is the leading cause of death globally. β-adrenergic signaling plays a pivotal role in the modulation of cardiac function in physiological and pathological conditions. Understanding the molecular mechanism of β-adrenergic signaling is fundamental for heart disease therapy. A recent discovery of Rad, a novel endogenous regulator of LTCC, brought new insights into the βAR-cAMP-PKA signaling pathway, and well explained the controversial evidence on the functional phosphorylation sites on LTCC subunits. It is well known that β1AR mediates global cAMP signaling while β2AR generates localized cAMP signaling. Recent findings suggest that β2AR may also blunt β1AR signaling through GRK2 mediated “offside compartmentalization” mechanism, which can also serve as a negative feed-forward mechanism preventing the cell toxicity of tonic β1AR activation by circulating catecholamines. This underscores the critical protective role of β2AR against the detrimental effects of β1AR overstimulation. Further discoveries of βAR signaling mechanisms will contribute to novel and effective diagnostic and therapeutic heart disease targets.

Conflict of interest

Bo Yang, Shi-Qiang Wang and Hua-Qian Yang declare that they have no conflict of interest.

Compliance with Ethical Standards

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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