Adrenoceptors, α₁

α₁-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; [9]) are GPCR 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 antagonists considered selective 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.

Adrenoceptors, α₂

α₂-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; [9]) are GPCR activated by endogenous agonists with a relative potency of (-)-adrenaline > (-)-noradrenaline. UK14304 (brimonidine) and BHT920 are agonists selective for α₂-adrenoceptors relative to α₁-adrenoceptors. rauwolscine (9.0) and yohimbine (9.0) are antagonists selective for α₂-adrenoceptors relative to α₁-adrenoceptors. [³H]rauwolscine (1 nM), [³H]UK14304 (5 nM) and [³H]RX821002 (0.5 nM and 0.1 nM at α_2C) are relatively selective radioligands. There is species variation in the pharmacology of the α_2A-adrenoceptor; for example, yohimbine, rauwolscine and oxymetazoline have an ~20-fold lower affinity for rat, mouse and bovine α_2A-adrenoceptors compared to the human receptor. These α_2A orthologues are sometimes referred to as α_2D-adrenoceptors. Multiple mutations of α₂-adrenoceptors have been described, some of which are associated with alterations in function. The effects of classical (not subtype selective) α₂-adrenoceptor agonists such as clonidine, guanabenz and UK14304 (brimonidine) on central baroreflex control (hypotension and bradycardia), hypnotic, analgesic, seizure modulation and platelet aggregation are mediated by α_2A-adrenoceptors. The roles of α_2B and α_2C-adrenoceptors are less clear but the α_2B subtype appears to be involved in neurotransmission in the spinal cord and α_2C in regulating catecholamine release from adrenal chromaffin cells.

Adrenoceptors, β

β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, [9]) are GPCR 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 by high concentrations of bupranolol (pK_i 8.65,[52]). 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 disease susceptibility and altered responses to drugs. The X-ray crystal structures have recently been described of the agonist bound [60] and antagonist bound forms of the β₁- [59], agonist-bound [13] and antagonist-bound forms of the β₂-adrenoceptor [47,49], as well as agonist-bound, G_s protein-coupled β₂-adrenoceptor [48].

Adrenoceptors, α₁

The clone originally called the α_1C-adrenoceptor corresponds to the pharmacologically defined α_1A-adrenoceptor [26]. 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 [20,43]). α_1A-Adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α_1L-adrenoceptor [46]. Recent studies suggest that the &alpha_1L - adenoceptor phenotype may result from the interaction of α_1A- adrenoceptors with cysteine-rich epidermal growth factor-like domain 1α (CRELD1α) [44]. α_1D-Adrenoceptors form heterodimers with α_1B- or β₂-adrenoceptors that show increased cell-surface expression [57]. Heterodimers formed between α_1D- and α_1B-adrenoceptors have distinct functional properties [24]. 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 and G_12/13. Several ligands activating α_1A-adrenoceptors display ligand directed signalling bias. For example, oxymetazoline is a full agonist for extracellular acidification rate (ECAR) and a partial agonist for Ca²⁺ release but does not stimulate cAMP production. phenylephrine is biased toward ECAR versus Ca²⁺ release or cAMP accumulation but not between Ca²⁺ release and cAMP accumulation [18]. There are also differences between subtypes in coupling efficiency to different pathways – e.g. 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.

Adrenoceptors, α₂

oxymetazoline is a reduced efficacy agonist. ARC-239 (pK_i 8.0) and prazosin (pK_i 7.5) show selectivity for α_2B- and α_2C-adrenoceptors over α_2A-adrenoceptors. Binding sites for imidazolines, distinct from α₂-adrenoceptors, have been identified and classified as I₁, I₂ and I₃ sites and catecholamines have a low affinity for these sites. I₁-imidazoline receptors are involved in central inhibition of sympathetic tone, I₂-imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I₃-imidazoline receptors regulate insulin secretion from pancreatic β-cells.

Adrenoceptors, β

(-)-noradrenaline, xamoterol and (-)-Ro 363 are agonists that show selectivity for β₁- relative to β₂-adrenoceptors. Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors [52]. All β-adrenoceptors couple to G_s (activating adenylyl cyclase and elevating cAMP 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, CGP 12177 and carazolol). Many ‘antagonists’ appear to be able to selectively activate mitogen-activated protein kinase pathways [5,19,22-23,51-52] and display ligand-directed signalling bias. bupranolol appears to act as a neutral antagonist in most systems so far examined. SR59230A has reasonably high affinity at β₃-adrenoceptors [39], but does not discriminate well between the three β-adrenoceptor subtypes [10] and has been reported to have lower affinity for the β₃-adrenoceptor in some circumstances [34].

The β₃-adrenoceptor has introns, but splice variants have only been described for the mouse [17], where the isoforms display different signalling characteristics [28]. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors [3]. The 'putative β₄-adrenoceptor' is not a novel receptor but is likely to represent an alternative site of interaction of CGP 12177 and other nonconventional partial agonists at β₁-adrenoceptors, since 'putative β₄-adrenoceptor'-mediated agonist effects of CGP 12177 are absent in mice lacking β₁-adrenoceptors [33,36].

Radioligand binding with [¹²⁵I]ICYP can be used to define β₁- or β₂-adrenoceptors when conducted in the presence of a 'saturating' concentration of either 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 CGP 12177 to β₂-adrenoceptors in living cells has been described [6]. [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.

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