MOLECULAR PHARMACOLOGY OF ALPHA(2)-ADRENOCEPTOR SUBTYPES

a(2)-adrenergic receptors mediate many of the physiological actions of the endogenous catecholamines adrenaline and noradrenaline, and are t argets of several therapeutic agents. a(2)-adrenoceptor agonists are c urrently used as antihypertensives and as veterinary sedative anaesthe tics. They are also used experimentally in humans as adjuncts to anaes thesia, as spinal analgesics, and to treat opioid, nicotine and alcoho l dependence and withdrawal. Three human alpha(2)-adrenoceptor subtype genes have been cloned and designated alpha(2)-C10, alpha(2)-C4 and a lpha(2)-C2, according to their location on human chromosomes 10, 4 and 2. They correspond to the previously identified pharmacological recep tor subtypes alpha(2A), alpha(2C), and alpha(2B). The receptor protein s share only about 50% identity in their amino acid sequence, but some structurally and functionally important domains are very well conserv ed. The most obvious functionally important differences between the re ceptor subtypes are based on their different tissue distributions; e.g . the alpha(2)A subtype appears to be an important modulator of noradr energic neurotransmission in the brain. The three receptors bind most a(2)-adrenergic drugs with similar affinities, but some compounds (e.g , oxymetazoline) are capable of discriminating between the subtypes. C linically useful subtype selectivity cannot be achieved with currently available pharmaceutical agents. The second messenger pathways of the three receptors show many similarities, but small functional differen ces between the subtypes may turn out to have important pharmacologica l and clinical consequences. All a(2)-adrenoceptors couple to the pert ussis-toxin sensitive inhibitory G proteins G(i) and G(o), but recent evidence indicates that also other G proteins may interact with a(2)-a drenoceptors, including G(s) and G(q/11). Inhibition of adenylyl cycla se activity, which results in decreased formation of cAMP, is an impor tant consequence of a(2)-adrenoceptor activation. Many of the physiolo gical activation cannot, however, be explained by decreases in cAMP fo rmation. Therefore, alternative mechanisms have been sought to account for the various effects of a(2)-adrenoceptor activation on electrophy siologic, secretory and contractile cellular responses. Recent results obtained from studies on ion channel regulation point to the importan ce of calcium and potassium channels in the molecular pharmacology of a(2)-adrenoceptors.