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J Biol Chem, Vol. 274, Issue 50, 35469-35474, December 10, 1999

Constitutive G_i2-dependent Activation of Adenylyl Cyclase Type II by the 5-HT1A Receptor
INHIBITION BY ANXIOLYTIC PARTIAL AGONISTS^*

Paul R. Albert, Naghmeh Sajedi, Sylvie Lemonde^§, and Mohammad H. Ghahremani^¶

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 G_i 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 G_s-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_i2, but not G_i1, G_i3, or G_o, resulted in an agonist-independent 6-fold increase in the basal cAMP level, suggesting that G_i2 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.

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^* 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.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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