Reciprocality Between Estrogen Biology and Calcium Signaling in the Cardiovascular System

Abstract

17β-Estradiol (E 2 ) is the main estrogenic hormone in the body and exerts many cardiovascular protective effects. Via three receptors known to date, including estrogen receptors α (ERα) and β (ERβ) and the G protein-coupled estrogen receptor 1 (GPER, aka GPR30), E 2 regulates numerous calcium-dependent activities in cardiovascular tissues. Nevertheless, effects of E 2 and its receptors on components of the calcium signaling machinery (CSM), the underlying mechanisms, and the linked functional impact are only beginning to be elucidated. A picture is emerging of the reciprocality between estrogen biology and Ca 2+ signaling. Therein, E 2 and GPER, via both E 2 -dependent and E 2 -independent actions, moderate Ca 2+ -dependent activities; in turn, ERα and GPER are regulated by Ca 2+ at the receptor level and downstream signaling via a feedforward loop. This article reviews current understanding of the effects of E 2 and its receptors on the cardiovascular CSM and vice versa with a focus on mechanisms and combined functional impact. An overview of the main CSM components in cardiovascular tissues will be first provided, followed by a brief review of estrogen receptors and their Ca 2+ -dependent regulation. The effects of estrogenic agonists to stimulate acute Ca 2+ signals will then be reviewed. Subsequently, E 2 -dependent and E 2 -independent effects of GPER on components of the Ca 2+ signals triggered by other stimuli will be discussed. Finally, a case study will illustrate how the many mechanisms are coordinated to moderate Ca 2+ -dependent activities in the cardiovascular system.

The G-Protein–Coupled Estrogen Receptor Agonist G-1 Inhibits Proliferation and Causes Apoptosis in Leukemia Cell Lines of T Lineage

“…Activation of 7TMR often leads to a Ca 2+ response (Gudermann and Bader, 2015). Such an effect has been observed when activating the GPER (Revankar et al, 2005;Ariazi et al, 2010;Dennis et al, 2011;Luo et al, 2014;Ding et al, 2019;Vo et al, 2019;Tran 2020). In our experiments, G-1 caused a rapid increase in [Ca 2+ ] c , which was initially mediated by the Ca 2+ release from the endoplasmic reticulum through the IP3R channel, followed by a prolonged influx of Ca 2+ from the extracellular space (Figure 3), most likely due to the activation of so named store-operated calcium entry (SOCE), which is the main Ca 2+ entry channel in lymphocytes (Zweifach and Lewis, 1993).…”

Calcium and calcium-related proteins in endometrial cancer: opportunities for pharmacological intervention

“…Likewise, E2 promoted CACNA1D expression in a time-dependent and dose-dependent manner and triggered Ca 2+ influx through GPER1 in breast cancer cells [45]. GPER1 regulates the activity of L-type VGCCs through coupling with Gαs and Gαi/o and triggers subsequent Ca 2+ entry [43]. GPER1 can also be directly regulated by the Ca 2+ -calmodulin complex because of the existence of four distinct calmodulin-binding domains in GPER1, as feedback to the E2-induced calcium increase [46].…”

“…As a novel estrogen receptor, GPER1 is reported to participate in estrogen-triggered non-genomic effects in ovarian cancer [40], ER-negative breast cancer [41] and thyroid cancer cells [42]. GPER1 can regulate intracellular free calcium by (1) activating membrane ion channels, (2) regulating Ca 2+calmodulin interactions or (3) triggering Ca 2+ store release [43,44]. In endometrial cancer cells, the GPER agonist G1 facilitated the expression of CACNA1D, while E2-BSA-activated CACNA1D was blocked after silencing the GPER1 gene [8].…”

Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females

“…The observed sex differences in Trpc channel expression in response to doxorubicin and Trpc6 -deficiency suggest that estrogen is not only cardioprotective, but perhaps the mechanism of estrogen-related cardioprotection is mediated through TRPC-related calcium signaling in the heart. Regulation of TRPC gene expression by estrogen was first reported in 1997 ( 61 ) and both E 2 and the G-protein estrogen receptor (GPER) act to moderate calcium-activities in the cardiovascular system by lowering the peaks and raising the troughs, thus refining calcium levels to a more narrow and sustained operating range [reviewed in ( 62 )]. Taken together, these data suggest that TRPC6 inhibition may serve as a potential cardioprotective therapy for male and post-menopausal female cancer patients that require doxorubicin.…”