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Abstract
α2adrenergic receptors mediate many of the physiological actions of the endogenous catecholamines adrenaline and noradrenaline, and are targets of several therapeutic agents, α2-adrenoceptor agonists are currently used as antihypertensives and as veterinary sedative anaesthetics. They are also used experimentally in humans as adjuncts to anaesthesia, as spinal analgesics, and to treat opioid, nicotine and alcohol dependence and withdrawal. Three human α2-adrenoceptor subtype genes have been cloned and designated α2-C10, α2-C4 and α2-C2, according to their location on human chromosomes 10, 4 and 2. They correspond to the previously identified pharmacological receptor subtypes α2A, α2C and α2B. The receptor proteins share only about 50% identity in their amino acid sequence, but some structurally and functionally important domains are very well conserved. The most obvious functionally important differences between the receptor subtypes are based on their different tissue distributions; e.g. the α2A subtype appears to be an important modulator of noradrenergic neurotransmission in the brain. The three receptors bind most α2-adrenergic drugs with similar affinities, but some compounds (e.g. oxymetazoline) are capable of discriminating between the subtypes. Clinically 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 differences between the subtypes may turn out to have important pharmacological and clinical consequences. All α2-adrenoceptors couple to the pertussis-toxin sensitive inhibitory G proteins Gi and Go, but recent evidence indicates that also other G proteins may interact with α2-adrenoceptors, including Gs and Gq/11. Inhibition of adenylyl cyclase activity, which results in decreased formation of cAMP, is an important consequence of α2-adrenoceptor activation. Many of the physiological effects of α2-adenoceptor activation cannot, however, be explained by decreases in cAMP formation. Therefore, alternative mechanisms have been sought to account for the various effects of α2-adrenoceptor activation on electrophysiologic, secretory and contractile cellular responses. Recent results obtained from studies on ion channel regulation point to the importance of calcium and potassium channels in the molecular pharmacology of α2-adrenoceptors.