Perspectives in Pharmacology In Vivo Gene Modification Elucidates Subtype-Specific Functions of a2-Adrenergic Receptors 1

Mice with altered a2-adrenergic receptor genes have become important tools in elucidating the subtype-specific functions of the three a2-adrenergic receptor subtypes because of the lack of sufficiently subtype-selective pharmacological agents. Mice with a deletion (knockout) of the a2A-, a2B-, or a2C-gene as well as a point mutation of the a2A-gene (a2A-D79N) and a 3-fold overexpression of the a2C-gene have been generated. Studies with these mice indicate that most of the classical functions mediated by the a2-adrenergic receptor, such as hypotension, sedation, analgesia, hypothermia, and anesthetic-sparing ef-fect, are mediated primarily by the a2A-subtype. The a2B-sub-type is the principal mediator of the hypertensive response to a2-agonists, appears to play a role in salt-induced hyperten-sion, and may be important in developmental processes. Th