RT Journal Article SR Electronic T1 The Guanine Nucleotide Exchange Factor vav2 is a Negative Regulator of PTH-receptor / Gq-signaling JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.078824 DO 10.1124/mol.112.078824 A1 Alexander Emami-Nemini A1 Antje Gohla A1 Henning Urlaub A1 Martin J. Lohse A1 Christoph Klenk YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/05/03/mol.112.078824.abstract AB The parathyroid hormone receptor 1 (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone (PTH) and related peptides via the activation of phospholipase C-β, adenylyl cyclase, mitogen-activated protein kinases and β-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is realized. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C-terminus, we have identified vav2, a guanine-nucleotide exchange factor (GEF) for Rho GTPases, as a PTHR interacting protein. The core domains of vav2 bound to the intracellular domains of the PTHR independent of receptor activation. In addition, vav2 specifically interacted with activated Gαq, but not with Gαs subunits, and it competed with PTHR for coupling to Gαq. Consistent with its specific interaction with Gαq, vav2 impaired Gq-mediated inositol phosphate generation, but not Gs-mediated cAMP generation. This inhibition of Gq-signaling was specific for PTHR-signaling when compared with other Gq-coupled GPCRs. Moreover, the benefit for PTHR-mediated inositol phosphate generation in the absence of vav2 required the ezrin binding domain of NHERF1. Our results show that a RhoA GEF can specifically interact with a GPCR and thereby modulate its G protein signaling specificity.