Molecular characterization

The adrenoceptors belong to the large family of 7-transmembrane-spanning, G protein coupled receptors, and there is 32-54% amino acid identity between the individual adrenoceptor proteins (Fig. 12.1). This receptor family was originally subdivided on the basis of pharmacological differentiation years before individual subtypes were cloned. In this respect, the demonstration that prejunctional effects had a different pharmacological profile from actions mediated by postjunctional a-adrenoceptors, such as vascular contraction, originally led to the division of a-adrenoceptors into the a1- and a2-subtypes (Langer 1974; Starke etal. 1974). The most likely sites for interaction of the catecholamines with conserved structural elements of the adrenoceptors have been identified (Strader et al. 1994) and are referred to in Chapter 1.

Three distinct a1 -adrenoceptor proteins have been cloned; after some confusion in nomenclature, it has now been established that these three recombinant a1-adrenoceptors, which are designated as a1a, a1b, and a1d, correspond to the pharmacologically defined a1A, a1B, and a1D adrenoceptors in native tissues (Hieble et al. 1995b). Multiple splice variants of the a1a-adrenoceptor have been identified; however they appear to have identical pharmacological characteristics (Chang et al. 1998). An additional a1-adrenoceptor, designated as the a1L-adrenoceptor, appears to mediate the contraction of several vascular and urogenital tissues. This receptor has not been cloned, and recent evidence suggests that the a1a-adrenoceptor may have either a1A- or a1L-pharmacology, depending on the particular assay, tissue, or experimental conditions employed (Ford etal. 1997). Three a2-adrenoceptor

Fig. 12.1 Structural similarity, based on overall amino acid identity, between the nine adrenoceptors. Based on this similarity, the adrenoceptors can be divided into three groups (a1, a2, P), with each group further divided into three subtypes. Structural similarity is higher (45-55 per cent identity) within either of the three groups than between individual members of different groups (33-40 per cent identity).

proteins have been cloned. These recombinant receptors, designated as a2a, a2b, and a2c, result in four discrete pharmacological profiles, since the a2a-adrenoceptor appears to exist as species orthologs, with those of human, pig, and rabbit having a profile designated as a2A, while those of rat, mouse, guinea pig, and cow exhibit pharmacologic profiles designated as a2D. Three ^-adrenoceptor proteins have been cloned, and the characteristics of these recombinant receptors correspond with those of the three well characterized ^-adrenoceptors on native tissues, designated as p1, p2, and p3.

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