Constitutively active Gq/11-coupled receptors enable signaling by co-expressed Gi/o-coupled receptors

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-HT1BR), 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-HT1BR agonists and inhibited by a selective inverse 5-HT1BR agonist. Interestingly, inverse H1R agonists inhibit constitutively H1R-mediated as well as 5-HT1BR agonist-induced signaling in cells co-expressing both receptors. This phenomenon is not solely characteristic of 5-HT1BR; it is also evident with muscarinic M-2 and adenosine A(1) receptors and is mimicked by mastoparan-7, an activator of G(i/o) proteins, or by over-expression of Gbetagamma 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.