PT  - JOURNAL ARTICLE
AU  - Kjetil Wessel Andressen
AU  - Jens Henrik Norum
AU  - Finn Olav Levy
AU  - Kurt A. Krobert
TI  - Activation of Adenylyl Cyclase by Endogenous G<sub>s</sub>-Coupled Receptors in Human Embryonic Kidney 293 Cells Is Attenuated by 5-HT<sub>7</sub> Receptor Expression
AID  - 10.1124/mol.105.015396
DP  - 2006 Jan 01
TA  - Molecular Pharmacology
PG  - 207--215
VI  - 69
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/69/1/207.short
4100  - http://molpharm.aspetjournals.org/content/69/1/207.full
SO  - Mol Pharmacol2006 Jan 01; 69
AB  - 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 Gi/o and Gq/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 Gs-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-HT4(b) and 5-HT7(a,b,d) receptor expression on adenylyl cyclase (AC) stimulation by the endogenous Gs-coupled β-adrenergic (βAR) and prostanoid EP (EPR) receptors. βAR- and EPR-stimulated AC activity was attenuated by 5-HT7 receptor expression in both membrane preparations and intact HEK293 cells. βAR- and EPR-stimulated AC activity was unaffected by expression of the Gs-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) βAR- and EPR-stimulated AC activity was not restored to control values when Gαs was overexpressed; and 2) β1AR and β2AR activation of Gαs was unaffected by the expression of 5-HT7 receptors. In addition, overexpression of AC isoforms was unable to rescue βAR- and EPR-stimulated AC activity. Therefore, 5-HT7 receptors probably limit access and/or impede activation of AC by βAR and EP receptors. Although the 5-HT7 receptor may preassociate with G protein and/or AC, the mechanism of this heterologous desensitization remains elusive.