Constitutively active G sub(q/11)-coupled Receptors Enable Signaling by Co-expressed G sub(i/o)-coupled Receptors

• Published in: The Journal of biological chemistry 2004-02, Vol.279 (7), p.5152-5161
• Main Authors: Bakker, R A, Casarosa, P, Timmerman, H, Smit, MJ, Leurs, R
• Format: Article
• Language: English
• Subjects: Human cytomegalovirus
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309200200

Co-expression of guanine nucleotide-binding regulatory (G) protein-coupled receptors (GPCRs), such as the G sub(i/o)-coupled human 5-hydroxytryptamine receptor 1B (5-HT sub(1B)R), with the G sub(q/11)-coupled human histamine 1 receptor (H sub(1)R) results in an overall increase in agonist-independent signaling, which can be augmented by 5-HT sub(1B)R agonists and inhibited by a selective inverse 5- HT sub(1B)R agonist. Interestingly, inverse H sub(1)R agonists inhibit constitutively H sub(1)R-mediated as well as 5-HT sub(1B)R agonist-induced signaling in cells co-expressing both receptors. This phenomenon is not solely characteristic of 5-HT sub(1B)R; it is also evident with muscarinic M sub(2) and adenosine A sub(1) receptors and is mimicked by mastoparan-7, an activator of G sub(i/o) proteins, or by over-expression of G[beta][gamma] subunits. Likewise, expression of the G sub(q/11)-coupled human cytomegalovirus (HCMV)-encoded chemokine receptor US28 unmasks a functional coupling of G sub(i/o)-coupled CCR1 receptors that is mediated via the constitutive activity of receptor US28. Consequently, constitutively active G sub(q/11)-coupled receptors, such as the H sub(1)R and HCMV-encoded chemokine receptor US28, constitute a regulatory switch for signal transduction by G sub(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.