The RH domain of GRK2 is involved in endothelin receptor desensitization

RIPOLL, SONIA; ECHEVERRIA, EMILIANA; TORRALBA-AGU, VALERIA; MONCZOR, FEDERICO; FERNANDEZ, NATALIA

Mar del Plata

Congreso; LXVI Reunión Anual de la SAIC; 2021

Sociedad Argentina de Investigación Clínica

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide implicated in the pathophysiology of diabetes mellitus and hypertension via activation of the endothelin receptor A (ETA) and B (ETB). Both G protein-coupled receptors (GPCRs) couple to Gq and PLC signalling pathway. Previous reports suggested that ET receptors are desensitized by GPCRs kinase 2 (GRK2) but independently of its kinase activity and that negative regulation by ET-1 of insulin signalling may involve GRK2 and heterologous desensitization of insulin receptor. The purpose of this study was to determine molecular mechanisms underlying negative regulation of ET-1 response with particular attention to the possible involvement of RH domain of GRK2 as a first step to elucidate insulin resistance mediated by ET-1. To do that, we characterized Ca2+ response and desensitization to ET-1 in HEK293 cells transfected with GRK2 variants containing different GRK2 domains or mutants. We found that after 15 min of pre-treatment, cells are completely desensitized to ET-1 stimulation p