Emerging roles of GPER in diabetes and atherosclerosis

Abstract

The G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings on its roles in obesity, diabetes, and atherosclerosis, including GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed.

Keywords: GPER; atherosclerosis; diabetes; estrogen receptor; rapid signaling.

Figure 1. Agonists and antagonists with intrinsic activity mediating or inhibiting GPER signaling

Agonists and antagonists of GPER with intrinsic activity mediating or inhibiting GPER-mediated signaling. Green arrows: activation; red arrows: inhibition; Receptors are activated by natural (endogenous estrogen such as 17β-estradiol, 2-methoxyestradiol) as well as by phytoestrogens (such as equol, quercetin, genistein, zearalonone, resveratrol), highly stable environmental pollutants, also known as xenoestrogens (including atrazine, zearalonone, bisphenol A, nonylphenol, or DDT), SERMS, SERDs, or GPER-selective synthetic drugs. The synthetic GPER-selective compounds G15 and G36, the non-selective MIBE, and the estrogen metabolites 2-hydroxyestradiol (2 OH-E2) and estriol act as GPER antagonists. See text for explanation. * denotes synthetic compounds as opposed to natural substances; DDT, dichlorodiphenyltrichloroethane; SERM, selective estrogen receptor modulator; SERD, selective estrogen receptor downregulator. MIBE, ethyl 3-[5-(2-ethoxycarbonyl-1-methylvinyloxy)-1-methyl-1H-indol-3-yl]but-2-enoate).

Figure 2. Roles of GPER in physiology and disease

Metabolic, vascular, immunological, physiological, and pathophysiological functions of GPER in the brain, pancreas, adipose tissue, arterial vasculature, skeletal muscle, liver, and white blood cells. ? indicates functions attributed to estrogen activity, where the precise role or contribution of GPER is unknown or requires further study. Abbreviations used: ADCF, adipose-derived contracting factor; CNS, central nervous system; EDCF, endothelium-derived contracting factor; LDL, low-density lipoprotein; TG, triglycerides; VSMC, vascular smooth muscle cells.