Abstract
The G protein-coupled estrogen receptor 1 (GPER) produces cardioprotective effects. However, the underlying mechanisms are not well understood. We aimed to investigate the role of GPER in β adrenoceptor-mediated cardiac contraction and myocardial signaling. In anesthetized animals, intrajugular administration of isoproterenol produces a rapid and sustained rise in left ventricular pressure (LVP) and increases ectopic contractions. Administration of the GPER agonist G-1 during the plateau phase of isoproterenol-induced LVP increase rapidly restores LVP to baseline levels and reduces the frequency of ectopic contractions. In freshly isolated cardiomyocytes, isoproterenol potentiates electrically induced peak currents of L-type Ca2+ channels (LTCC) and increases the potential sensitivity of their inactivation. Coadministration of G-1 prevents isoproterenol-induced potentiation of peak LTCC currents and makes channels more sensitive to being inactivated compared to isoproterenol alone. Isoproterenol treatment of cardiomyocytes without electrical stimulation triggers slow-rising Ca2+ signals that are inhibited by the β1AR antagonist metoprolol but not by β2AR antagonist ICI-118551. G-1 pretreatment dose-dependently suppresses isoproterenol-induced total Ca2+ signals and the amplitude and frequency of the intrinsic Ca2+ oscillatory deflections. Pretreatment with the GPER antagonist G-36 produces opposite effects, dose-dependently increasing these signals. ISO promotes robust phosphorylation of Cav1.2 channels at Ser1928. G-1 pretreatment inhibits isoproterenol-stimulated phosphorylation of Cav1.2 at Ser1928, while G-36 pretreatment enhances this signal. Our data indicate that GPER functions as an intrinsic component of β1AR signaling to moderate myocardial Ca2+ dynamics and contraction.