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Activation of Adenylyl Cyclase by Endogenous G_s-Coupled Receptors in Human Embryonic Kidney 293 Cells Is Attenuated by 5-HT₇ Receptor Expression

Department of Pharmacology, University of Oslo, Oslo, Norway

Human 5-hydroxytryptamine₇ (5-HT₇) receptors display characteristics shared with receptors believed to form a tight physical coupling with G protein in the absence of ligand. Some receptors apparently preassociated with G_i/o and G_q/11 are reported to inhibit the signaling of other similarly coupled G protein-coupled receptors by limiting their access to activate a common G protein pool. Therefore, we determined whether 5-HT₇ receptor expression was sufficient to limit signaling of endogenously expressed G_s-coupled receptors in human embryonic kidney (HEK) 293 cells. Using the ecdysone-inducible expression system, which allows for the titration of increasing receptor density in the same clonal cell line, we compared the effects of 5-HT_4(b) and 5-HT_7(a,b,d) receptor expression on adenylyl cyclase (AC) stimulation by the endogenous G_s-coupled -adrenergic (AR) and prostanoid EP (EPR) receptors. AR- and EPR-stimulated AC activity was attenuated by 5-HT₇ receptor expression in both membrane preparations and intact HEK293 cells. AR- and EPR-stimulated AC activity was unaffected by expression of the G_s-coupled 5-HT₄ receptor. The mechanism of this heterologous desensitization seems independent of protein kinase A activation, nor does it occur at the level of G protein activation because 1) AR- and EPR-stimulated AC activity was not restored to control values when G_s was overexpressed; and 2) ₁AR and ₂AR activation of G_s was unaffected by the expression of 5-HT₇ receptors. In addition, overexpression of AC isoforms was unable to rescue AR- and EPR-stimulated AC activity. Therefore, 5-HT₇ receptors probably limit access and/or impede activation of AC by AR and EP receptors. Although the 5-HT₇ receptor may preassociate with G protein and/or AC, the mechanism of this heterologous desensitization remains elusive.

Address correspondence to: Dr. Finn Olav Levy, Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. E-mail: f.o.levy{at}medisin.uio.no