In vivo gene modification elucidates subtype-specific functions of alpha(2)-adrenergic receptors

Mice with altered alpha(2)-adrenergic receptor genes have become important tools in elucidating the subtype-specific functions of the three alpha(2)-a drenergic receptor subtypes because of the lack of sufficiently subtype-sel ective pharmacological agents. Mice with a deletion (knockout) of the alpha (2A)-, alpha(2B)-, or alpha(2C)-gene as well as a point mutation of the alp ha(2A)-gene (alpha(2A)-D79N) and a 3-fold overexpression of the alpha(2C)-g ene have been generated, Studies with these mice indicate that most of the classical functions mediated by the alpha(2)-adrenergic receptor, such as h ypotension, sedation, analgesia, hypothermia, and anesthetic-sparing effect , are mediated primarily by the alpha(2A)-subtype. The alpha(2B)-subtype is the principal mediator of the hypertensive response to alpha(2)-agonists, appears to play a role in salt-induced hypertension, and may be important i n developmental processes. The alpha(2C)-subtype appears to be involved in many central nervous system processes such as the startle reflex, stress re sponse, and locomotion. Both the alpha(2A)- and alpha(2C)-subtypes are impo rtant in the presynaptic inhibition of norepinephrine release and appear to have distinct regulatory roles. The ability to study subtype-specific func tions in different mouse strains by altering the same alpha(2)-adrenergic r eceptor in different ways strengthens the conclusions drawn from these stud ies. Although these genetic approaches have limitations, they have signific antly increased our understanding of the functions of alpha(2)-adrenergic r eceptor subtypes.