Activation of G protein‐coupled estrogen receptor 1 (GPER) induces coronary artery relaxation via cAMP/PKA pathway

Abstract

Activation of the membrane estrogen receptor, GPER, may lower high blood pressure and preserve cardiac function after reperfusion. We reported that GPER activation induces a rapid relaxation of porcine coronary arteries by opening of BKCa channels. However, downstream signaling events in this pathway are poorly understood. The objective of our study was to investigate the mechanism of GPER‐mediated coronary artery relaxation. We found that the adenylyl cyclase (AC) inhibitor, SQ‐22538 (100 μM), attenuated G‐1 (GPER agonist)‐induced relaxation of pre‐constricted porcine coronary arteries, and shifted the G‐1 concentration‐relaxation curve to the left. These findings suggest that AC plays functional role in GPER action. Furthermore, G‐1 (1μM) stimulated cAMP production, and this stimulation was blocked by 5 μM G15 (GPER selective antagonist). Treating arteries with 5μM Rp‐8CPT‐cAMP (PKA selective inhibitor) significantly inhibited the G‐1 relaxation effect, and shifted the concentration‐response curve to the left. Lastly, 100 μM FMP‐API‐1 (an inhibitor of the interaction between PKA and the A kinase anchoring protein, AKAP) attenuated the relaxation effect of G‐1. In conclusion, G‐1 induces porcine coronary artery relaxation via cAMP/PKA signaling, which involves subcellular localization of PKA via interaction with AKAP.