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Regulation of Myocardial Contraction and Ca 2+ Dynamics by the G Protein‐Coupled Estrogen Receptor
Author(s) -
Whitcomb Victoria
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.676.10
Subject(s) - gper , phospholamban , endocrinology , medicine , chemistry , metoprolol , preload , contraction (grammar) , receptor , agonist , estrogen receptor , antagonist , phenylephrine , blood pressure , calcium , hemodynamics , cancer , breast cancer
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 (β 1 AR). 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 Ca 2+ entry signals that are inhibited by β 1 AR antagonist metoprolol but not by b 2 ‐AR antagonist ICI‐118551. GPER activation using G‐1 (K d 11 nM) at 0.01, 0.1 and 1 mM suppresses the total Ca 2+ 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 (IC 50 112 nM) at 0.01, 0.1 and 1 mM increases isoproterenol‐induced total Ca 2+ 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 β 1 AR‐mediated Ca 2+ signaling in the myocardium and plays an important role in β 1 AR‐mediated cardiac contraction. Support or Funding Information National Institutes of Health Grant HL112184 and IOER 091707 to Quang‐Kim Tran; American Heart Association Grant 15SDG25090279 to Eric Wauson; IOER grant to Sarah Clayton This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .