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J Biol Chem, Vol. 274, Issue 50, 35469-35474, December 10, 1999
From the Neuroscience Research Institute, Departments of Medicine
and Cellular and Molecular Medicine, University of Ottawa, Ottawa,
Canada K1H 8M5 and the ¶ Department of Pharmacology and
Therapeutics, McGill University, Montreal, Canada H3G 1Y6
The 5-HT1A receptor is implicated in depression
and anxiety. This receptor couples to Gi proteins to
inhibit adenylyl cyclase (AC) activity but can stimulate AC in tissues
(e.g. hippocampus) that express ACII. The role of ACII in
receptor-mediated stimulation of cAMP formation was examined in HEK-293
cells transfected with the 5-HT1A receptor, which mediated inhibition
of basal and Gs-induced cAMP formation in the absence of
ACII. In cells cotransfected with 5-HT1A receptor and ACII plasmids,
5-HT1A agonists induced a 1.5-fold increase in cAMP level.
Cotransfection of 5-HT1A receptor, ACII, and G
Constitutive Gi2-dependent Activation of
Adenylyl Cyclase Type II by the 5-HT1A Receptor
INHIBITION BY ANXIOLYTIC PARTIAL AGONISTS*
,
i2, but
not Gi1, Gi3, or Go,
resulted in an agonist-independent 6-fold increase in the basal cAMP
level, suggesting that Gi2 preferentially coupled the
receptor to ACII. The 5-HT1B receptor also constitutively activated
ACII. Constitutive activity of the 5-HT1A receptor was blocked by
pertussis toxin and the G
antagonist, CT, suggesting an
important role for G-mediated activation of ACII. The Thr-149 
Ala mutation in the second intracellular domain of the 5-HT1A receptor
disrupted G-selective activation of ACII. Spontaneous 5-HT1A
receptor activity was partially attenuated by 5-HT1A receptor partial
agonists with anxiolytic activity (e.g. buspirone and flesinoxan) but was not altered by full agonists or antagonists. Thus,
anxiolytic activity may involve inhibition of spontaneous 5-HT1A
receptor activity.
*
This work was supported by grants from the Medical Research
Council, Canada and the National Cancer Institute, Canada.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Novartis/MRC Michael Smith Chair in Neurosciences. To whom
correspondence should be addressed: Neuroscience Research Institute, University of Ottawa, 451 Smyth Rd., Ottawa, Canada K1H 8M5. Tel.: 613-562-5800, ext. 8307; Fax: 613-562-5403; E-mail: palbert@
uottawa.ca.
§
MRC Scholar.
Supported by the Ministry of Iran and a Schizophrenia Society
of Canada scholarship.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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