Suppression of store-operated Ca2+ entry by activation of GPER: contribution to a clamping effect on endothelial Ca2+ signaling
- 23 October 2017
- journal article
- Published by Portland Press Ltd. in Biochemical Journal
- Vol. 474 (21), 3627-3642
- https://doi.org/10.1042/bcj20170630
Abstract
The G Protein-coupled Estrogen Receptor 1 (GPER, formerly a.k.a. GPR30) modulates many Ca2+-dependent activities in endothelial cells. However, the underlying mechanisms are poorly understood. We recently reported that GPER acts to prolong cytoplasmic Ca2+ signals by interacting with and promoting inhibitory phosphorylation of the plasma membrane Ca2+-ATPase. In this study, we examined the role of GPER activation in modulating store-operated Ca2+ entry (SOCE) via effects on the Stromal Interaction Molecule 1 (STIM1). GPER activation by agonist G-1 reduces the peak but prolongs the plateau of bradykinin-induced Ca2+ signals in primary endothelial cells. G-1 dose-dependently inhibits thapsigargin-induced SOCE measured by the Mn2+ quenching method. GPER heterologous expression reduces SOCE, which is further pronounced by G-1 treatment. Consistently, GPER gene silencing in endothelial cells is associated with an increase in SOCE. Treatment with G-1 reduces puncta formation by STIM1 triggered by activation of SOCE. The effect of GPER activation to inhibit SOCE is not affected by combined non-phosphorylatable substitutions at serines 486 and 668 on STIM1, but is substantially reduced by similar substitutions at serines 575, 608 and 621. Taken together with our recently reported inhibitory actions of GPER on Ca2+ efflux, the current data contribute to a model in which GPER acts to clamp agonist-induced cytoplasmic Ca2+ signals. Kinetic modeling based on current and reported data is used to estimate the overall effect of GPER activation on point activity of endothelial nitric oxide synthase during the time course of agonist-induced total Ca2+ signals.This publication has 49 references indexed in Scilit:
- Hetero-oligomeric Complex between the G Protein-coupled Estrogen Receptor 1 and the Plasma Membrane Ca2+-ATPase 4bOnline Journal of Public Health Informatics, 2015
- Improvement of Vascular Function by Acute and Chronic Treatment with the GPR30 Agonist G1 in Experimental Diabetes MellitusPLOS ONE, 2012
- GPR30 is positioned to mediate estrogen effects on basal forebrain cholinergic neurons and cognitive performanceBrain Research, 2011
- Estrogen Receptor Activation and Cardioprotection in Ischemia Reperfusion InjuryTrends in Cardiovascular Medicine, 2010
- Estradiol-mediated ERK phosphorylation and apoptosis in vascular smooth muscle cells requires GPR 30American Journal of Physiology-Cell Physiology, 2009
- Regulatory Role of G Protein–Coupled Estrogen Receptor for Vascular Function and ObesityCirculation Research, 2009
- GPR30: a novel therapeutic target in estrogen-related diseaseTrends in Pharmacological Sciences, 2008
- Virtual and biomolecular screening converge on a selective agonist for GPR30Nature Chemical Biology, 2006
- A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell SignalingScience, 2005
- Estrogen-Induced Activation of Erk-1 and Erk-2 Requires the G Protein-Coupled Receptor Homolog, GPR30, and Occurs via Trans-Activation of the Epidermal Growth Factor Receptor through Release of HB-EGFMolecular Endocrinology, 2000