VASCULAR ALPHA-ADRENOCEPTORS - FROM THE GENE TO THE HUMAN

Adrenoceptors can be subdivided into three major types, the alpha(1)-, alpha(2)-, and beta-adrenoceptors. Each of these types can be further subdivided into three subtypes, based on pharmacological characterist ics. Molecular cloning techniques have supported this subclassificatio n. Recent data now suggest that cr-adrenoceptor subtypes identified by pharmacological and molecular techniques correspond well, although sp ecies orthologs of several adrenoceptor subtypes have been identified. The secondary structure of the adrenoceptors has been elucidated and correlated with their interaction with second messenger molecules. alp ha(1)-Adrenoceptors, beta-adrenoceptors, and alpha(2)-adrenoceptors me diate their actions through stimulation of inositol phosphate release, stimulation of adenylate cyclase, and inhibition of adenylate cyclase , respectively. Site-directed mutagenesis and the preparation of chime ric receptors have located the site of receptor - second messenger int eraction to the third intracellular loop for each of these adrenocepto rs. While subtypes of each of these classes all interact with the same second messenger, studies with recombinant alpha(2)-adrenoceptors sho w subtype-related differences in receptor second messenger interaction . Multiple cr-adrenoceptor subtypes are expressed in vascular smooth m uscle and are involved in various aspects of blood vessel function, in cluding contraction, cellular growth, and proliferation. Various physi ological factors can selectively influence responses to a particular s ubtype, and the relative roles of each subtype can vary between vascul ar beds and along an individual blood vessel as its caliber changes. F unctional studies in blood vessels suggest the presence of additional alpha-adrenoceptor subtypes not yet identified via molecular technique s. Optimization of the therapeutic profile of an alpha-adrenoceptor an tagonist may be possible via enhancement of selectivity for a particul ar subtype or by design of a specific profile of affinity for the indi vidual subtypes.