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)-adrenergic receptor subtypes because of the lack of sufficiently subtype-selective 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 alpha(2A)-gene (alpha(2A)-D79N) and a 3-fold overexpression of the alpha(2C)-gene have been generated. Studies with these mice indicate that most of the classical functions mediated by the alpha(2)-adrenergic receptor, such as hypotension, 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 in developmental processes. The alpha(2C)-subtype appears to be involved in many central nervous system processes such as the startle reflex, stress response, and locomotion. Both the alpha(2A)- and alpha(2C)-subtypes are important in the presynaptic inhibition of norepinephrine release and appear to have distinct regulatory roles. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(2)-adrenergic receptor in different ways strengthens the conclusions drawn from these studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(2)-adrenergic receptor subtypes.
Kable
J W
JW
Department of Pharmacology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Murrin
L C
LC
Bylund
D B
DB
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2