Adrenoceptors, α₁

Overview:α₁-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors, Bylund et al., 1994) are 7TM receptors activated by the endogenous agonists adrenaline and noradrenaline with equal potency. Phenylephrine, methoxamine and cirazoline are agonists selective for α₁-adrenoceptors relative to α₂-adrenoceptors, while prazosin (8.5–10.5) and corynanthine (6.5–7.5) are considered selective antagonists for α₁-adrenoceptors relative to α₂-adrenoceptors. [³H]-Prazosin (0.25 nM) and [¹²⁵I]-HEAT (0.1 nM; also known as BE2254) are relatively selective radioligands. Numerous splice variants of the α₁-adrenoceptors exist, some of which may display a different spectrum of signalling properties. One polymorphism of the α_1A-adrenoceptor has been described but is not associated with disease.

Nomenclature	α1A	α1B	α1D
Other names	α1a, α1c	α1b	α1A/D, α1a/d
Ensembl ID	ENSG00000120907	ENSG00000170214	ENSG00000171873
Principal transduction	Gq/11	Gq/11	Gq/11
Selective agonists	A61603, dabuzalgron (Blue et al., 2004)	–	–
Selective antagonists	Tamsulosin (10.5), silodosin (10.4), (+)niguldipine (10.0), SNAP5089 (9.7)	–	BMY7378 (8.4)

The clone originally called the α_1C-adrenoceptor corresponds to the pharmacologically defined α_1A-adrenoceptor (see Ford et al., 1994; Hieble et al., 1995). Some tissues possess α_1A-adrenoceptors that display relatively low affinity in functional and binding assays for prazosin (pK_i < 9) that might represent different receptor states (termed α_1L-adrenoceptors, Ford et al., 1997; Morishima et al., 2007). α_1A-Adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α_1L-adrenoceptor (Ramsay et al., 2004). α_1D-Adrenoceptors form heterodimers with α_1B- or β₂-adrenoceptors that show increased cell-surface expression (Uberti et al., 2005). Heterodimers formed between α_1D- and α_1B-adrenoceptors have distinct functional properties (Hague et al., 2004). α_1D-Adrenoceptors are mainly located intracellularly. (+)Niguldipine also has high affinity for L-type Ca²⁺ channels.

Signalling is predominantly via G_q/11 but α₁-adrenoceptors also couple to G_i/o, G_s, G_12/13 and G_h. There are differences between subtypes in coupling efficiency to different pathways – for example coupling efficiency to Ca²⁺ signalling is α_1A > α_1B > α_1D, but for MAP kinase signalling is α_1D > α_1A > α_1B. The subtypes also seem to show differences in regulation.

Glossary

Abbreviations:

A61603

N-(5-[4,5-dihydro-1H-imidazol-2-y]-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)methanesulfonamide hydrobromide

BMY7378

8-(2-[4-{2methoxyphenyl}-1-piperazinyl]ethyl)-8-azaspiro[4,5]decane-7,9-dione dihydrochloride

HEAT

2-β-4-hydroxy-3-iodophenylethylaminomethyltetralone

RS17053

N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamide

silodosin

(-)-(R)-1-(3-hydroxypropyl)-5-(2-[2-{2-(2,2,2-trifluoroethoxy)phenoxyl}ethylamino]propyl)indoline-7-carboxamide, also known as KMD3213

SNAP5089

2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-N-[3-(4,4-diphenylpiperidin-1-yl)propyl]amide methyl ester

SNAP5272

5-carboxamide-2,6-diethyl-1,4-dihydro-3-[N-(3-[4-hydroxy-4-phenylpiperidinyl]propyl)]carboxamido-4-(4-nitrophenyl)

Further Reading

Andersson KE, Gratzke C (2007). Pharmacology of α₁-adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol4: 368–378.

Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP et al. (1994). International Union of Pharmacology IV. Nomenclature of adrenoceptors. Pharmacol Rev46: 121–136.

Cotecchia S (2007). Constitutive activity and inverse agonism at the α1adrenoceptors. Biochem Pharmacol73: 1076–1083.

Hein L (2006). Adrenoceptors and signal transduction in neurons. Cell Tissue Res326: 541–551.

Hein P, Michel MC (2007). Signal transduction and regulation: are all α₁-adrenergic receptor subtypes created equal? Biochem Pharmacol73: 1097–1106.

Hieble JP, Bylund DB, Clarke DE, Eikenburg DC, Langer SZ, Lefkowitz RJ et al. (1995). International Union of Pharmacology. X. Recommendation for nomenclature of α1-adrenoceptors: consensus update. Pharmacol Rev47: 267–270.

Koshimizu TA, Tanoue A, Tsujimoto G (2007). Clinical implications from studies of α1 adrenergic receptor knockout mice. Biochem Pharmacol73: 1107–1112.

Perez DM (2007). Structure-function of α₁-adrenergic receptors. Biochem Pharmacol73: 1051–1062.

Tanoue A, Koshimizu TA, Shibata K, Nasa Y, Takeo S, Tsujimoto G (2003). Insights into α1 adrenoceptor function in health and disease from transgenic animal studies. Trends Endocrinol Metab14: 107–113.