Regulation of Myocardial Contraction and Ca2+ Dynamics by the G Protein‐Coupled Estrogen Receptor

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The G protein‐coupled estrogen receptor (GPER) mediates many cardioprotective effects. However, the underlying mechanisms are not clear.We investigated the role of GPER in cardiac contraction and signaling mediated by the cardiac b1 adrenergic receptor (β1AR). In anesthetized female rats, intrajugular administration of isoproterenol produces rapid and sustained increase in left ventricular systolic pressure (LVSBP) from 100±9 mmHg to 160±12 mmHg and a mild decrease in LV end diastolic pressure (LVEDP) from 10±5 mmHg to 5±5 mmHg. Administration of GPER agonist G‐1 during the plateau phase of the isoproterenol‐induced pressure rise rapidly reduces LVSBP to 90±5 mmHg and LVEDP to 0±5 mmHg. In freshly isolated primary murine cardiomyocytes, isoproterenol triggers oscillatory Ca2+ entry signals that are inhibited by β1AR antagonist metoprolol but not by b2‐AR antagonist ICI‐118551. GPER activation using G‐1 (Kd 11 nM) at 0.01, 0.1 and 1 mM suppresses the total Ca2+ signals by 0.5±0.3, 17.6±2 (p<0.05), and 30±2.1% (p<0.05), the amplitude of oscillations by 12.6±1.2, 36.6±7.1 (p<0.05), and 42.5±5.2% (p<0.05), and the frequency of oscillatory deflections by 0±0.8, 28.6±4.2 (p <0.05), and 30.3±5.4 (p<0.05), respectively. Isoproterenol promotes robust phosphorylation of the CaV1.2 channels at Ser1928 and phospholamban at Ser16/Thr17. G‐1 at 0.01, 0.1 and 1 mM prevents the former by 11.3±1.24, 28.4±2.3 (p<0.05) and 49.3±6.1%, and the latter by 5.3 ± 0.9, 22.3 ± 3.3 (p<0.05) and 42.5 ± 5.2%, respectively. Interestingly, GPER inhibition with G‐36 (IC50 112 nM) at 0.01, 0.1 and 1 mM increases isoproterenol‐induced total Ca2+ signals by 1±0.7, 26±2.5 (p<0.05) and 59.3±3.1% (p<0.05), oscillatory amplitude by 26±5.3, 129±21 (p<0.05) and 294±9.6% (p<0.05), and oscillatory frequency by 22.8±7.6, 59.1±8 (p<0.05) and 92±13% (p<0.05), respectively. G‐36 pretreatment at 0.01, 0.1 and 1 mM enhances isoproterenol‐stimulated Cav1.2 Ser1928 phosphorylation by 1.45±0.93, 27±9.6, and 47.8±7.1% (p<0.05), and phospholamban Ser16/Thr17 phosphorylation by 23.6±5.3, 53.3±17.5, and 32.2±5.6% (p<0.05), respectively.Taken together, the data suggest that GPER activation is an intrinsic component of β1AR‐mediated Ca2+ signaling in the myocardium and plays an important role in β1AR‐mediated cardiac contraction.Support or Funding InformationNational Institutes of Health Grant HL112184 and IOER 091707 to Quang‐Kim Tran; American Heart Association Grant 15SDG25090279 to Eric Wauson; IOER grant to Sarah ClaytonThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.