Abstract
17β-Estradiol (E2) 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), E2 regulates numerous calcium-dependent activities in cardiovascular tissues. Nevertheless, effects of E2 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 Ca2+ signaling. Therein, E2 and GPER, via both E2-dependent and E2-independent actions, moderate Ca2+-dependent activities; in turn, ERα and GPER are regulated by Ca2+ at the receptor level and downstream signaling via a feedforward loop. This article reviews current understanding of the effects of E2 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 Ca2+-dependent regulation. The effects of estrogenic agonists to stimulate acute Ca2+ signals will then be reviewed. Subsequently, E2-dependent and E2-independent effects of GPER on components of the Ca2+ signals triggered by other stimuli will be discussed. Finally, a case study will illustrate how the many mechanisms are coordinated to moderate Ca2+-dependent activities in the cardiovascular system.
Highlights
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), E2 regulates numerous calcium-dependent activities in cardiovascular tissues
Therein, E2 and GPER, via both E2-dependent and E2-independent actions, moderate Ca2+-dependent activities; in turn, ERα and GPER are regulated by Ca2+ at the receptor level and downstream signaling via a feedforward loop
Do Ca2+ signals stimulated by estrogenic agonists activate Ca2+dependent activities? When reported, the concentration of a Ca2+ signal allows for prediction of proteins that may or may not be affected by it
Summary
Ca2+ and mitochondria house ∼25% [3]. The Golgi [4, 5] and lysosomes have more recently been recognized as Ca2+ reservoirs [6, 7]. Uniporter; MEK1, MAP (mitogen-activated protein) kinase/ERK (extracellular signal-regulated kinase) kinase 1; mPTP, mitochondrial permeability transition pore; NCX, Na+-Ca2+ exchanger; OVX, ovariectomy/ovariectomized; PDZ, PSD-95/Dlg/ZO; PKC, protein kinase C; PLCβ, phospholipase C-β; PMCA, plasma membrane Ca2+-ATPase; PSD-95, post-synaptic density protein 95; RMP, resting membrane potential; RyRs, ryanodine receptors; SCPA, secretory pathway Ca2+ pump; SERCA, sarcoplasmic/endoplasmic reticulum-ATPase; SMD, submembrane domains of G protein-coupled receptors; SOCE, storeoperated Ca2+ entry; SOICR, store overload-induced Ca2+ release; SR/ER, sarcoendoplasmic reticulum; STIM1, stromal interaction molecule 1; VDAC, voltagedependent anion channel; VDCC, voltage-dependent Ca2+ channels; VDCE, voltage-dependent Ca2+ entry; VSMCs, vascular smooth muscle cells Such as K+, Na+, and Ca2+ into the mitochondria [24]. Mutations that reduce CaM binding but that do not perturb GPERGβγ preassociation drastically prevent GPER-mediated ERK1/2 phosphorylation [170]
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