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J. Biol. Chem., Vol. 279, Issue 7, 5152-5161, February 13, 2004

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Constitutively active G_q/11-coupled Receptors Enable Signaling by Co-expressed G_i/o-coupled Receptors^*

Remko A. Bakker, Paola Casarosa, Henk Timmerman, Martine J. Smit, and Rob Leurs¶

From the Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands

Co-expression of guanine nucleotide-binding regulatory (G) protein-coupled receptors (GPCRs), such as the G_i/o-coupled human 5-hydroxytryptamine receptor 1B (5-HT_1BR), with the G_q/11-coupled human histamine 1 receptor (H₁R) results in an overall increase in agonist-independent signaling, which can be augmented by 5-HT_1BR agonists and inhibited by a selective inverse 5-HT_1BR agonist. Interestingly, inverse H₁R agonists inhibit constitutively H₁R-mediated as well as 5-HT_1BR agonist-induced signaling in cells co-expressing both receptors. This phenomenon is not solely characteristic of 5-HT_1BR; it is also evident with muscarinic M₂ and adenosine A₁ receptors and is mimicked by mastoparan-7, an activator of G_i/o proteins, or by over-expression of G subunits. Likewise, expression of the G_q/11-coupled human cytomegalovirus (HCMV)-encoded chemokine receptor US28 unmasks a functional coupling of G_i/o-coupled CCR1 receptors that is mediated via the constitutive activity of receptor US28. Consequently, constitutively active G_q/11-coupled receptors, such as the H₁R and HCMV-encoded chemokine receptor US28, constitute a regulatory switch for signal transduction by G_i/o-coupled receptors, which may have profound implications in understanding the role of both constitutive GPCR activity and GPCR cross-talk in physiology as well as in the observed pathophysiology upon HCMV infection.

Received for publication, August 19, 2003 , and in revised form, October 7, 2003.

^* This research was supported in part by UCB Pharma (Belgium) and the European Union BIOMED 2 program, "Inverse Agonism, Implications for Drug Research." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Altana Nederland.

Supported by the Royal Dutch Academy of Arts and Sciences.

^¶ To whom correspondence should be addressed. Tel.: 31-20-444-7579; Fax: 31-20-444-7610; E-mail: leurs{at}few.vu.nl.

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