Adrenoceptors, β

Overview:β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, Bylund et al., 1994) are 7TM receptors, activated by the endogenous agonists adrenaline and noradrenaline. Isoprenaline is a synthetic agonist selective for β-adrenoceptors relative to α₁- and α₂-adrenoceptors, while propranolol (pK_i 8.2–9.2) and cyanopindolol (pK_i 10.0–11.0) are relatively selective antagonists. β₃-Adrenoceptors are relatively resistant to blockade by propranolol (pK_i 5.8–7.0), but can be blocked with high concentrations of cyanopindolol (pK_i 9.0). Numerous polymorphisms exist for the β₁- and β₂-adrenoceptors and some of these are associated with alterations in signalling in response to agonists. These polymorphisms are likely to be associated with altered responses to drugs. The X-ray crystal structures of the β₁- (Warne et al., 2008) and β₂-adrenoceptors (Cherezov et al., 2007) have been solved.

Nomenclature	β1	β2	β3
Other names	–	–	atypical β
Ensembl ID	ENSG00000043591	ENSG00000169252	ENSG00000147477
Principal transduction	Gs	Gs	Gs
Rank order of potency	Noradenaline > adrenaline	Adrenaline > noradenaline	Noradenaline = adrenaline
Selective agonists	Noradrenaline, xamoterol, RO363, denopamine	Procaterol, zinterol, salmeterol, formoterol, terbutaline, fenoterol	BRL37344, CL316243, CGP12177A, carazolol, L742791, SB251023
Selective antagonists	CGP20712A (8.5–9.3), betaxolol (8.5), atenolol (7.6)	ICI118551 (8.3–9.2)	SR59230A (8.8), L748328 (8.5)
Probes	[125I]-ICYP (20–50 pM) + 70 nM ICI118551	[125I]-ICYP (20–50 pM) + 100 nM CGP20712A	[125I]-ICYP (0.5 nM)

Noradrenaline, xamoterol and RO363 show selectivity for β₁- relative to β₂-adrenoceptors. All β-adrenoceptors couple to G_s (activating adenylyl cyclase and elevating cyclic AMP levels), but it is also clear that they activate other G proteins such as G_i and many other signalling pathways, particularly mitogen-activated protein kinases. Many antagonists at β₁- and β₂-adrenoceptors are agonists at β₃-adrenoceptors (CL316243, CGP12177A and carazolol). Many ‘antagonists’ appear to be able to selectively activate mitogen-activated protein kinase pathways (Baker et al., 2003a; Galandrin and Bouvier, 2006; Sato et al., 2007; Galandrin et al., 2008; Sato et al., 2008). SR59230A has reasonably high affinity at β₃-adrenoceptors (Manara et al., 1996), but does not discriminate well between the three β-adrenoceptor subtypes (Candelore et al., 1999) and has been reported to have lower affinity for the β₃-adrenoceptor in some circumstances (Kaumann and Molenaar, 1996).

Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the ‘rodent selective’ agonists BRL37344 and CL316243 have low efficacy at the human β₃-adrenoceptor. The β₃-adrenoceptor has introns, but splice variants have only been described for the mouse (Evans et al., 1999). The β-adrenoceptor cloned from turkey (termed the β4c, t428 SwissProt P43141) has a pharmacology that is intermediate between β₂- and β₃-adrenoceptors (Chen et al., 1994). The ‘putative β₄-adrenoceptor’ is not a novel receptor but is likely to represent an alternative site of interaction of CGP12177A and other nonconventional partial agonists at β₁-adrenoceptors, as ‘putative β₄-adrenoceptor’-mediated agonist effects of CGP12177A are absent in mice lacking β₁-adrenoceptors (Konkar et al., 2000; Kaumann et al., 2001).

Radioligand binding to define β₁- and β₂-adrenoceptors can be conducted in the presence of a ‘saturating’ concentration of a β₁- or β₂-adrenoceptor-selective antagonist. [³H]-CGP12177 or [³H]-dihydroalprenolol can be used in place of [¹²⁵I]-ICYP. Binding of a fluorescent analogue of CGP12177 to β₂-adrenoceptors in living cells has been described (Baker et al., 2003b). [¹²⁵I]-ICYP at higher (nM) concentrations can be used to label β₃-adrenoceptors in systems where there are few if any other β-adrenoceptor subtypes.

Glossary

Abbreviations:

BRL37344

sodium 4-(2-[2-hydroxy-3-chlorophenyl}ethylamino]propyl)phenoxyacetate

CGP12177A

(-)-4-(3-tert-butylamino-2-hydroxypropoxy)-benzimidazol-2-one

CGP20712A

2-hydroxy-5-(2-[{2-hydroxy-3-(4-[1-methyl-4-trifluoromethyl-2-imidazolyl]phenoxy)propyl}amino]ethoxy)benzamide

CL316243

disodium (R,R)-5-(2-[{2-(3-chlorophenyl)-2-hydroxyethyl}-amino]propyl)-1,3-benzodioxole-2,2,dicarboxylate

ICYP

iodocyanopindolol

L742791

(S)-N-(4-[2-{(3-[4-hydroxyphenoxy]-2-hydroxypropyl)amino}ethyl]phenyl)-4-iodobenzenesulfonamide

L748328

(S)-N-(4-[2-{(3-[3-{aminosulfonyl}phenoxy]-2-hydroxypropyl)-amino}ethyl]phenyl)benzenesulfonamide

RO363

(-)-1-(3,4-dimethoxyphenethylamino)-3-(3,4-dihdroxyphenoxy)-2-propanol)oxalate

SB251023

(4-[1-{2-(S)-hydroxy-3-(4-hydroxyphenoxy)-propylamino}cyclopentylmethyl]phenoxymethyl)phenylphosphonic acid lithium salt

SR59230A

3-(2-ethylphenoxy)-1([1s]-1,2,3,4-tetrahydronaphth-1-ylamino)-2S-propanol oxalate

Further Reading

Ahles A, Engelhardt S (2009). Polymorphisms determine β-adrenoceptor conformation: implications for cardiovascular disease and therapy. Trends Pharmacol Sci30: 188–193.

Brodde OE (2008). β₁ and β₂ adrenoceptor polymorphisms: Functional importance, impact on cardiovascular diseases and drug responses. Pharmacol Ther117: 1–29.

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.

Kaumann AJ, Molenaar P (2008). The low-affinity site of the β₁-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacol Ther118: 303–336.

Mustafi D, Palczewski K (2009). Topology of class A G protein-coupled receptors: insights gained from crystal structures of rhodopsins, adrenergic and adenosine receptors. Mol Pharmacol75: 1–12.

Philipp M, Hein L (2004). Adrenergic receptor knockout mice: distinct functions of 9 receptor subtypes. Pharmacol Ther101: 65–74.

Rosenbaum DM, Rasmussen SG, Kobilka BK (2009). The structure and function of G-protein-coupled receptors. Nature459: 356–363.