title: Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice.
abstract: alpha2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of alpha2-ARs have been cloned (alpha2A, alpha2B, and alpha2C). Here we describe the physiological consequences of disrupting the gene for the alpha2A-AR. Mice lacking functional alpha2A subtypes were compared with wild-type (WT) mice, with animals lacking the alpha2B or alpha2C subtypes, and with mice carrying a point mutation in the alpha2A-AR gene (alpha2AD79N). Deletion of the alpha2A subtype led to an increase in sympathetic activity with resting tachycardia (knockout, 581 +/- 21 min-1; WT, 395 +/- 21 min-1), depletion of cardiac tissue norepinephrine concentration (knockout, 676 +/- 31 pg/mg protein; WT, 1178 +/- 98 pg/mg protein), and down-regulation of cardiac beta-ARs (Bmax: knockout, 23 +/- 1 fmol/mg protein; WT, 31 +/- 2 fmol/mg protein). The hypotensive effect of alpha2 agonists was completely absent in alpha2A-deficient mice. Presynaptic alpha2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective alpha2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from alpha2B-AR knockout, alpha2C-AR knockout, alpha2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the alpha2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual alpha2-mediated effect in the alpha2A-AR knockout mice suggests that a second alpha2 subtype (alpha2B or alpha2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.
authors.affiliation: Howard Hughes Medical Institute, Stanford University, Stanford, California, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Altman
authors.forename: A U
authors.initials: AU
authors.lastname: Trendelenburg
authors.forename: L
authors.initials: L
authors.lastname: MacMillan
authors.forename: D
authors.initials: D
authors.lastname: Bernstein
authors.forename: L
authors.initials: L
authors.lastname: Limbird
authors.forename: K
authors.initials: K
authors.lastname: Starke
authors.forename: B K
authors.initials: BK
authors.lastname: Kobilka
authors.forename: L
authors.initials: L
authors.lastname: Hein
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism; D015536:Down-Regulation; D017353:Gene Deletion; D006339:Heart Rate; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D017661:Receptors, Presynaptic / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D013610:Tachycardia / Q000209:etiology
chemical_list: D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D017661:Receptors, Presynaptic; D009638:Norepinephrine