Substitution of a mutant α2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo
- Parul P. Lakhlani*,†,
- Leigh B. MacMillan*,†,
- Tian Zhi Guo‡,
- Brian A. McCool,
- David M. Lovinger,
- Mervyn Maze‡, and
- Lee E. Limbird†,¶
- Departments of †Pharmacology and ‡Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232; *Department of Anesthesia, Stanford University, Stanford, CA 94305; and the Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304
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Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA, and approved July 7, 1997 (received for review April 3, 1997)
Abstract
Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and α2 adrenergic receptor (α2AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each α2AR subtype (α2A, α2B, and α2C) plays in these central effects. Here we demonstrate that α2AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated α2AAR, D79N α2AAR, created by two-step homologous recombination. These functional changes are accompanied by failure of the D79N α2AAR to inhibit voltage-gated Ca2+ currents and spontaneous neuronal firing, a measure of K+ current activation. These results provide definitive evidence that the α2AAR subtype is the primary mediator of clinically important central actions of α2AR agonists and suggest that the D79N α2AAR mouse may serve as a model for exploring other possible α2AAR functions in vivo.
Footnotes
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↵ * P.P.L. and L.B.M. contributed equally to this study.
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↵ ¶ To whom reprint requests should be addressed. e-mail: Lee.Limbird{at}mcmail.vanderbilt.edu.
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This paper was submitted directly (Track II) to the Proceedings Office.
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Abbreviations: α2AR, α2-adrenergic receptor; cDNA or genes encoding the α2AR subtypes are designated as α2aAR, α2bAR, and α2cAR; the pharmacologically defined subtype proteins are designated as α2AAR, α2BAR, and α2CAR; CNS, central nervous system; WT, wild-type; dex, dexmedetomidine; LC, locus ceruleus; LORR, loss of righting reflex; MHPG, 3-methoxy-4-hydroxyphenylethylene glycol; NE, norepinephrine; SCG, superior cervical ganglion; DAMGO, [d-Ala2, N-McPhe4, Gly5-ol]enkephalin.
- Copyright © 1997, The National Academy of Sciences of the USA
