Abnormal Regulation of the Sympathetic Nervous System in α2A-Adrenergic Receptor Knockout Mice (original) (raw)
Research ArticleArticle
, Anne U. Trendelenburg, Leigh MacMillan, Dan Bernstein, Lee Limbird, Klaus Starke, Brian K. Kobilka and Lutz Hein
Molecular Pharmacology July 1999, 56 (1) 154-161; DOI: https://doi.org/10.1124/mol.56.1.154
Abstract
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.
Footnotes
Received December 4, 1999.
Accepted March 19, 1999.
Send reprint requests to: Brian K. Kobilka, M.D., Howard Hughes Medical Institute, B-157 Beckman Center, Stanford University Medical Center, Stanford, CA 94305. E-mail: kobilka{at}cmgm.stanford.edu
This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 355 (to M.J.L. in support of L.H.) and SFB 1523 (to A.U.T. and K.S.) and the Howard Hughes Medical Institute (to B.K.).
The American Society for Pharmacology and Experimental Therapeutics
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