title: Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes.
abstract: In the adrenergic system, release of the neurotransmitter norepinephrine from sympathetic nerves is regulated by presynaptic inhibitory alpha2-adrenoceptors, but it is unknown whether release of epinephrine from the adrenal gland is controlled by a similar short feedback loop. Using gene-targeted mice we demonstrate that two distinct subtypes of alpha2-adrenoceptors control release of catecholamines from sympathetic nerves (alpha 2A) and from the adrenal medulla (alpha 2C). In isolated mouse chromaffin cells, alpha2-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca2+ current, as well as secretion of epinephrine and norepinephrine. The inhibitory effects of alpha2-agonists on cell capacitance, voltage-activated Ca2+ currents, and on catecholamine secretion were completely abolished in chromaffin cells isolated from alpha 2C-receptor-deficient mice. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (alpha 2A-knockout) and epinephrine levels (alpha 2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels. Thus, receptor subtype diversity in the adrenergic system has emerged to selectively control sympathetic and adrenal catecholamine secretion via distinct alpha2-adrenoceptor subtypes. Short-loop feedback inhibition of epinephrine release from the adrenal gland may represent a novel therapeutic target for diseases that arise from enhanced adrenergic stimulation.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Gabor
authors.initials: G
authors.lastname: Nagy
authors.forename: Melanie
authors.initials: M
authors.lastname: Philipp
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Sorensen
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Lohse
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000068438:Brimonidine Tartrate; D020013:Calcium Signaling / Q000502:physiology; D002395:Catecholamines / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism; D004837:Epinephrine / Q000097:blood / Q000378:metabolism / Q000652:urine; D005089:Exocytosis / Q000502:physiology; D025461:Feedback, Physiological; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism / Q000652:urine; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C547769:Adra2a protein, mouse; C547775:Adra2c protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D002395:Catecholamines; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D000068438:Brimonidine Tartrate; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine; D004837:Epinephrine