TY - JOUR T1 - Arginine Vasopressin Enhances Cell Survival Via a GRK2-βarrestin1-ERK1/2-Dependent Pathway in H9c2 Cells JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.113.086322 SP - mol.113.086322 AU - Weizhong Zhu AU - Douglas G Tilley AU - Valerie D Myers AU - Ryan C Coleman AU - Arthur M Feldman Y1 - 2013/05/20 UR - http://molpharm.aspetjournals.org/content/early/2013/05/20/mol.113.086322.abstract N2 - Circulating levels of arginine vasopressin (AVP) are elevated during hypovolemia and during cardiac stress. AVP activates V1A-Gαq coupled receptors in the heart and vasculature and V2-Gαs coupled receptors in the kidney. However, little is known regarding the signaling pathways that influence the effects of V1A receptor (V1AR) activation during cellular injury. Using hypoxia-reoxygenation (H/R) as a cell injury model, we evaluated cell survival and caspase 3/7 activity in H9c2 myoblasts after treatment with AVP. Pretreatment of H9c2 cells with AVP significantly reduced H/R-induced cell death and caspase 3/7 activity, effects that were blocked via both selective V1AR inhibition and MEK1/2 inhibition. AVP increased ERK1/2 phosphorylation in a concentration-dependent manner that was sensitive to MEK1/2 inhibition and V1AR inhibition, but not V1BR or V2R inhibition. Discrete elements of the V1A-Gαq-protein kinase C (PKC) and V1A-G protein-coupled receptor kinase (GRK)-β-arrestin signaling cascades were inhibited in order to dissect the pathways responsible for the protective effects of V1AR signaling: Gαq (over-expression of GqI), PKC (administration of Ro 31-82425), GRK2 (βARKct overexpression and siRNA knockdown), GRK5 (siRNA knockdown) and β-arrestin1 (siRNA knockdown). These studies demonstrated that both Gαq/PKC- and GRK2/β-arrestin1-dependent V1AR signaling were capable of inducing ERK1/2 phosphorylation in response to AVP stimulation. However, AVP-mediated protection against H/R was elicited only via GRK2- and β-arrestin1-dependent signaling. These results suggest that activation of the V1AR in H9c2 cells mediates protective signaling via a GRK2-β-arrestin1-ERK1/2-dependent mechanism that leads to decreased caspase 3/7 activity and enhanced survival under conditions of ischemic stress. ER -