PT  - JOURNAL ARTICLE
AU  - Alexander Emami-Nemini
AU  - Antje Gohla
AU  - Henning Urlaub
AU  - Martin J. Lohse
AU  - Christoph Klenk
TI  - The Guanine Nucleotide Exchange Factor Vav2 Is a Negative Regulator of Parathyroid Hormone Receptor/G<sub>q</sub> Signaling
AID  - 10.1124/mol.112.078824
DP  - 2012 Aug 01
TA  - Molecular Pharmacology
PG  - 217--225
VI  - 82
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/82/2/217.short
4100  - http://molpharm.aspetjournals.org/content/82/2/217.full
SO  - Mol Pharmacol2012 Aug 01; 82
AB  - The parathyroid hormone receptor (PTHR) is a class B G protein-coupled receptor (GPCR) that mediates the endocrine and paracrine effects of parathyroid hormone and related peptides through the activation of phospholipase Cβ-, adenylyl cyclase-, mitogen-activated protein kinase-, and β-arrestin-initiated signaling pathways. It is currently not clear how specificity among these downstream signaling pathways is achieved. A possible mechanism involves adaptor proteins that affect receptor/effector coupling. In a proteomic screen with the PTHR C terminus, we 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, 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 Na+/H+-exchanger regulatory factor 1. Our results show that a RhoA GEF can specifically interact with a GPCR and modulate its G protein signaling specificity.