Review
Subtypes of functional α1- and α2-adrenoceptors

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Abstract

In this review, subtypes of functional α1- and α2-adrenoceptors are discussed. These are cell membrane receptors, belonging to the seven transmembrane spanning G-protein-linked family of receptors, which respond to the physiological agonists noradrenaline and adrenaline. α1-Adrenoceptors can be divided into α1A-, α1B- and α1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A 4th α1-adrenoceptor, the α1L-, has been postulated to mediate contractions in some tissues, but its relationship to cloned receptors remains to be established. α2-Adrenoceptors can be divided into α2A-, α2B- and α2C-adrenoceptors, all of which mediate contractile responses. Prejunctional inhibitory α2-adrenoceptors are predominantly of the α2A-adrenoceptor subtype (the α2D-adrenoceptor is a species orthologue), although α2C-adrenoceptors may also occur prejunctionally. Although α2-adrenoceptors are linked to inhibition of adenylate cyclase, this may not be the primary signal in causing smooth muscle contraction; likewise, prejunctional inhibitory actions probably involve restriction of Ca2+ entry or opening of K+ channels. Receptor knock-out mice are beginning to refine our knowledge of the functions of α-adrenoceptor subtypes.

Introduction

Adrenoceptors can be defined as the cell membrane receptors, belonging to the seven transmembrane spanning G-protein-linked family of receptors, which respond to the physiological agonists noradrenaline and adrenaline by producing a response in the cell. Adrenoceptors can be divided into two broad categories, α and β, or more correctly into three major sub-categories, α1, α2 and β, although this review will concentrate on α1- and α2-adrenoceptors. α-Adrenoceptors have been one of the most widely studied families of receptor because of the major physiological importance of these receptors in control of blood pressure and blood flow, neural modulation, digestion, micturition, airways, reproduction, pupil diameter, endocrine and metabolic processes and in behaviour.

Historically, Ahlquist (1948)described two types of adrenoceptor based on the rank order of potency of a series of agonists. The receptor termed β was mainly inhibitory, except in the heart, and the receptor termed α was mainly excitatory, except in the intestine. In Ahlquist's classification, α-adrenoceptors were receptors present on smooth muscle, i.e., postjunctional α-adrenoceptors.

The next major development in adrenoceptor classification did not occur until 1974, but the starting point for this was an article by Brown and Gillespie (1957)which demonstrated that the α-adrenoceptor antagonists dibenamine and phenoxybenzamine increased the release of neurotransmitter from cat spleen. In hindsight, similar observations had been made by Bacq and Frederico in 1934 (Bacq and Frederico, 1934) but were overlooked. These findings were initially explained in terms of potentiation of release of noradrenaline due to blockade of the neuronal noradrenaline transporter (Thoenen et al., 1964), but Starke et al. (1971)demonstrated that the α-adrenoceptor antagonist phentolamine increased stimulation-evoked noradrenaline release by an action distinct from uptake blockade. Since the α-adrenoceptor agonists xylazine (Heise et al., 1971) and clonidine (Starke et al., 1972) were then found to reduce the stimulation-evoked release of noradrenaline from adrenergic nerve terminals, it became clear that these actions of α-adrenoceptor agonists and antagonists were mediated by α-adrenoceptors on the nerve terminals, so called presynaptic or prejunctional receptors (see Starke, 1977). It is now well established that prejunctional receptors for a large number of neurotransmitters and neuromodulators are present on many kinds of nerve terminals. Prejunctional α-heteroceptors on non-adrenergic nerves mediate inhibition of transmission in those nerves, but, more interestingly, prejunctional α-autoreceptors on adrenergic nerves mediate a negative feedback whereby released noradrenaline modulates its own further release (for reviews, see Langer, 1974, Langer, 1997; Westfall, 1977; Starke, 1977, Starke, 1987).

Once the concept of prejunctional and postjunctional α-adrenoceptors had been accepted, it became clear that there were differences between pre- and postjunctional α-adrenoceptors in terms of the relative potencies of a series of agonists and antagonists. This led to the subclassification of α-adrenoceptors into α1-postjunctional and α2-prejunctional adrenoceptors (Langer, 1974). Later, when evidence accumulated for α2-adrenoceptors located postjunctionally, this purely anatomical classification was refined into a pharmacological subclassification, independent of location (Berthelsen and Pettinger, 1977; Starke and Langer, 1979). Perhaps most surprisingly, α2-adrenoceptors were shown to occur on vascular smooth muscle and to mediate vasoconstrictor responses (Drew and Whiting, 1979; Docherty et al., 1979; Docherty and McGrath, 1980). Initially, it was suggested that these α2-adrenoceptors may be predominantly extrasynaptic and mediate responses to circulating catecholamines (Langer et al., 1981), but it later became clear that contractions to nerve stimulation in human saphenous vein and other tissues are also α2-adrenoceptor mediated (Docherty and Hyland, 1985).

Further advances in our understanding of α-adrenoceptors have come from the development of new pharmacological methodologies for the study of receptors. The first of these was the technique of the radioligand binding assay which, beginning in the mid-1980's, began to demonstrate that there were subtypes of both α1-adrenoceptors (see Morrow and Creese, 1986; Han et al., 1987) and α2-adrenoceptors (see Bylund, 1985, Bylund, 1988). However, the relationship between ligand binding sites and functional receptors was not always easy to ascertain (see Docherty, 1989). The study of α-adrenoceptors was revolutionised by the techniques of molecular biology. Six genes for α-adrenoceptors have now been identified and sequenced (α1A, α1B, α1D, α2A, α2B, α2C) and species orthologues have been identified (human α2A and rat α2D: see Bylund et al., 1994; Hieble et al., 1995). Studies of subtypes of receptor have been made easy by transfection of genes into suitable cell lines to produce pure populations of recombinant receptors.

Fig. 1 shows how the subclassification of α-adrenoceptors has developed since 1948.

The object of this short review is to look at functional subtypes of α-adrenoceptors, their physiological roles, and at some problems remaining in terms of subclassification. Rather than discuss α1- and α2-adrenoceptors independent of location, I have chosen to investigate pre- and postjunctional receptors separately to allow a more logical consideration of function.

Section snippets

Prejunctional α2A/D-adrenoceptors

α2-Adrenoceptors have been subdivided into three subtypes, α2A-, α2B- and α2C-adrenoceptors, based on ligand binding and molecular cloning studies (Lorenz et al., 1990; Bylund, 1992), and the rat α2D-adrenoceptor is a species orthologue of the human α2A-adrenoceptor (Lanier et al., 1991; Harrison et al., 1991). Functional prejunctional α2-adrenoceptors in rat submandibular gland (Limberger et al., 1992; Smith et al., 1992a; Smith and Docherty, 1992), rat vas deferens (Smith et al., 1992a; Smith

α1-Adrenoceptor subtypes

α1-Adrenoceptors were initially subdivided into α1A and α1B-subtypes in ligand binding studies, based on the affinities of a series of ligands, especially WB 4101 and prazosin (Morrow and Creese, 1986), and based on the ability of the alkylating agent chloroethylclonidine to inactivate the α1B but not the α1A subtype (Han et al., 1987). Under this classification, functional receptors mediating contractions of rat vas deferens are α1A, and those of rat spleen (excluding α2-adrenoceptors) are α1B

Postjunctional α-adrenoceptors and ageing

Responsiveness of vascular α1-adrenoceptors has been widely studied in relation to ageing; however, most studies have failed to find any change with age in contractile responses of isolated blood vessels or in pressor responses to agonists. Contractile responses to α1-adrenoceptor agonists may be influenced by altered function of the vascular endothelium so that an increased responsiveness to α1-adrenoceptor agonists of rat tail artery with age can be explained by diminished vasodilator

Physiological responses mediated by α1-adrenoceptors

Piascik et al. (1990)reported that the α1A-subtype played a role in the tonic maintenance of blood pressure in the conscious rat, whereas the α1B-subtype participates in the response to exogenous agonists. In knock-out mice lacking the α1B-adrenoceptor subtype, there was no effect on basal blood pressure, but the pressor response to phenylephrine were significantly blunted (Cavalli et al., 1997). These results may suggest that both α1A- and α1B-adrenoceptors are involved in blood pressure

Conclusion

The characteristics of α1- and α2-adrenoceptor subtypes are summarised in Table 1, Table 2. Although a great deal is known about the function of α-adrenoceptor subtypes, a number of major questions remain to be answered: the identity of the α1L-response; the second messengers involved in a significant number of responses; therapeutic potential of the development of receptor subtype selective agonists and antagonists. Mutant mice, in which receptor genes have been manipulated preventing

Acknowledgements

Work carried out in the author's laboratory was supported by RCSI and the Health Research Board (Ireland).

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