title: Constitutively active Gq/11-coupled receptors enable signaling by co-expressed G(i/o)-coupled receptors.
abstract: 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(1B)R), 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(1B)R agonists and inhibited by a selective inverse 5-HT(1B)R agonist. Interestingly, inverse H1R agonists inhibit constitutively H1R-mediated as well as 5-HT(1B)R agonist-induced signaling in cells co-expressing both receptors. This phenomenon is not solely characteristic of 5-HT(1B)R; 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 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.
authors: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors: Remko A
authors: RA
authors: Bakker
authors: Paola
authors: P
authors: Casarosa
authors: Henk
authors: H
authors: Timmerman
authors: Martine J
authors: MJ
authors: Smit
authors: Rob
authors: R
authors: Leurs
mesh_terms: D000818:Animals; D019556:COS Cells; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008954:Models, Biological; D010455:Peptides; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000737:chemistry* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014862:Wasp Venoms / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D007295:Inositol Phosphates; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010455:Peptides; D043682:Receptor, Adenosine A1; D043585:Receptor, Muscarinic M2; D044302:Receptor, Serotonin, 5-HT1B; D043562:Receptors, G-Protein-Coupled; D014862:Wasp Venoms; C037500:mastoparan; D004247:DNA; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11