Alpha2-adrenoceptor subtypes--unexpected functions for receptors and ligands derived from gene-targeted mouse models.
Alpha2-adrenoceptors belong to the group of nine adrenoceptors which mediate the biological actions of the endogenous catecholamines adrenaline and noradrenaline. Studies with gene-targeted mice carrying deletions in the genes encoding alpha2A-, alpha2B- or alpha2C-adrenoceptors have provided new insight into adrenergic receptor biology: (1) In principle, all three alpha2-receptor subtypes may operate as presynaptic inhibitory feedback receptors to control the release of noradrenaline and adrenaline or other transmitters from neurons. (2) Pharmacological effects of non-selective alpha2-ligands could be assigned to specific receptor subtypes, e.g. hypotension, sedation and analgesia are mediated via alpha2A-receptors. (3) Alpha2-adrenoceptor deficient mice have helped to uncover novel and unexpected functions of these receptor, e.g. feedback control of catecholamine release via alpha2C-receptors in adrenal chromaffin cells and control of angiogenesis during embryonic development. (4) Additional pharmacological targets for alpha2-adrenoceptor ligands were identified, e.g. inhibition of cardiac HCN2 and HCN4 pacemaker channels by clonidine.
Institute of Experimental and Clinical Pharmacology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
Anne E
AE
Knaus
Verena
V
Muthig
Stefanie
S
Schickinger
Eduardo
E
Moura
Nadine
N
Beetz
Ralf
R
Gilsbach
Lutz
L
Hein
D000818:Animals; D019439:Chromaffin Cells / Q000378:metabolism; D018390:Gene Targeting; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics*; D017661:Receptors, Presynaptic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
C547769:Adra2a protein, mouse; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic