PT  - JOURNAL ARTICLE
AU  - John D. Altman
AU  - Anne U. Trendelenburg
AU  - Leigh MacMillan
AU  - Dan Bernstein
AU  - Lee Limbird
AU  - Klaus Starke
AU  - Brian K. Kobilka
AU  - Lutz Hein
TI  - Abnormal Regulation of the Sympathetic Nervous System in α<sub>2A</sub>-Adrenergic Receptor Knockout Mice
AID  - 10.1124/mol.56.1.154
DP  - 1999 Jul 01
TA  - Molecular Pharmacology
PG  - 154--161
VI  - 56
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/56/1/154.short
4100  - http://molpharm.aspetjournals.org/content/56/1/154.full
SO  - Mol Pharmacol1999 Jul 01; 56
AB  - α2-Adrenergic receptors (ARs) play a key role in regulating neurotransmitter release in the central and peripheral sympathetic nervous systems. To date, three subtypes of α2-ARs have been cloned (α2A, α2B, and α2C). Here we describe the physiological consequences of disrupting the gene for the α2A-AR. Mice lacking functional α2Asubtypes were compared with wild-type (WT) mice, with animals lacking the α2B or α2C subtypes, and with mice carrying a point mutation in the α2A-AR gene (α2AD79N). Deletion of the α2A 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 β-ARs (B max: knockout, 23 ± 1 fmol/mg protein; WT, 31 ± 2 fmol/mg protein). The hypotensive effect of α2 agonists was completely absent in α2A-deficient mice. Presynaptic α2-AR function was tested in two isolated vas deferens preparations. The nonsubtype-selective α2 agonist dexmedetomidine completely blocked the contractile response to electrical stimulation in vas deferens from α2B-AR knockout, α2C-AR knockout, α2AD79N mutant, and WT mice. The maximal inhibition of vas deferens contraction by the α2 agonist in α2A-AR knockout mice was only 42 ± 9%. [3H]Norepinephrine release studies performed in vas deferens confirmed these findings. The results indicate that the α2A-AR is a major presynaptic receptor subtype regulating norepinephrine release from sympathetic nerves; however, the residual α2-mediated effect in the α2A-AR knockout mice suggests that a second α2 subtype (α2B or α2C) also functions as a presynaptic autoreceptor to inhibit transmitter release.