Department of Physiology and Pharmacology, Des Moines University Osteopathic Medical Center, 3200 Grand Avenue, Des Moines, IA 50312, United States.
Department of Physiology and Pharmacology, Des Moines University Osteopathic Medical Center, 3200 Grand Avenue, Des Moines, IA 50312, United States.
Biochem Pharmacol. 2020 Jan;171:113727. doi: 10.1016/j.bcp.2019.113727. Epub 2019 Nov 21.
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 Ca 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 Ca signals that are inhibited by the βAR antagonist metoprolol but not by βAR antagonist ICI-118551. G-1 pretreatment dose-dependently suppresses isoproterenol-induced total Ca signals and the amplitude and frequency of the intrinsic Ca oscillatory deflections. Pretreatment with the GPER antagonist G-36 produces opposite effects, dose-dependently increasing these signals. ISO promotes robust phosphorylation of Ca1.2 channels at Ser1928. G-1 pretreatment inhibits isoproterenol-stimulated phosphorylation of Ca1.2 at Ser1928, while G-36 pretreatment enhances this signal. Our data indicate that GPER functions as an intrinsic component of βAR signaling to moderate myocardial Ca dynamics and contraction.
G 蛋白偶联雌激素受体 1（GPER）具有心脏保护作用。然而，其潜在机制尚不清楚。我们旨在研究 GPER 在β肾上腺素受体介导的心脏收缩和心肌信号转导中的作用。在麻醉动物中，颈内静脉给予异丙肾上腺素可迅速而持续地升高左心室压力（LVP）并增加异位收缩。在异丙肾上腺素诱导的 LVP 升高的平台期给予 GPER 激动剂 G-1 可迅速将 LVP 恢复到基线水平并减少异位收缩的频率。在新鲜分离的心肌细胞中，异丙肾上腺素增强了 L 型钙通道（LTCC）的电诱导峰值电流，并增加了其失活的电位敏感性。G-1 的共给药可防止异丙肾上腺素诱导的 LTCC 峰值电流的增强，并使通道对失活的敏感性比异丙肾上腺素单独处理时更高。未经电刺激的心肌细胞中异丙肾上腺素的处理会触发缓慢上升的 Ca 信号，该信号被βAR 拮抗剂美托洛尔抑制，但不受βAR 拮抗剂 ICI-118551 的抑制。G-1 的预处理剂量依赖性地抑制异丙肾上腺素诱导的总 Ca 信号以及内在 Ca 振荡偏移的幅度和频率。GPER 拮抗剂 G-36 的预处理会产生相反的效果，剂量依赖性地增加这些信号。ISO 促进 Ca1.2 通道在 Ser1928 处的强烈磷酸化。G-1 的预处理抑制异丙肾上腺素刺激的 Ca1.2 在 Ser1928 处的磷酸化，而 G-36 的预处理增强了该信号。我们的数据表明，GPER 作为βAR 信号的内在组成部分发挥作用，以调节心肌 Ca 动力学和收缩。
