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Vol. 56, Issue 1, 154-161, July 1999
2A-Adrenergic Receptor Knockout Mice
Howard Hughes Medical Institute, Stanford University, Stanford,
California (J.D.A., B.K.K.); Institut für Pharmakologie,
Universität Freiburg, Freiburg, Germany (A.U.T., K.S.);
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
(L.M., L.L.); Division of Pediatric Cardiology, Stanford University,
Stanford, California (D.B.); and Institut für Pharmakologie,
Universität Würzburg, Würzburg, Germany (L.H.)
2-Adrenergic receptors (ARs) play a key role in
regulating neurotransmitter release in the central and peripheral
sympathetic nervous systems. To date, three subtypes of
2-ARs have been cloned (2A,
2B, and 2C). Here we describe the
physiological consequences of disrupting the gene for the
2A-AR. Mice lacking functional 2A
subtypes were compared with wild-type (WT) mice, with animals lacking
the 2B or 2C subtypes, and with mice
carrying a point mutation in the 2A-AR gene
(2AD79N). Deletion of the 2A subtype led
to an increase in sympathetic activity with resting tachycardia (knockout, 581 ± 21 min
1; WT, 395 ± 21 min1), depletion of cardiac tissue norepinephrine
concentration (knockout, 676 ± 31 pg/mg protein; WT, 1178 ± 98 pg/mg protein), and down-regulation of cardiac 
-ARs
(Bmax: knockout, 23 ± 1 fmol/mg protein;
WT, 31 ± 2 fmol/mg protein). The hypotensive effect of
2 agonists was completely absent in
2A-deficient mice. Presynaptic 2-AR function was tested in two isolated vas deferens preparations. The
nonsubtype-selective 2 agonist dexmedetomidine
completely blocked the contractile response to electrical stimulation
in vas deferens from 2B-AR knockout,
2C-AR knockout, 2AD79N mutant, and WT
mice. The maximal inhibition of vas deferens contraction by the
2 agonist in 2A-AR knockout mice was only
42 ± 9%. [3H]Norepinephrine release studies
performed in vas deferens confirmed these findings. The results
indicate that the 2A-AR is a major presynaptic receptor
subtype regulating norepinephrine release from sympathetic nerves;
however, the residual 2-mediated effect in the
2A-AR knockout mice suggests that a second
2 subtype (2B or 2C) also
functions as a presynaptic autoreceptor to inhibit transmitter release.
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