4.5 Review

What have we learned about GPER function in physiology and disease from knockout mice?

Journal

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2015.06.014

Keywords

Estrogen; Receptors; Cancer; Metabolism; Obesity; Cardiovascular; Immune; Diabetes

Funding

  1. NIH [CA116662, CA118743, CA127731, CA163890]
  2. UNM Cancer Center [P30 CA118100]

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Estrogens, predominantly 17 beta-estradiol, exert diverse effects throughout the body in both normal and pathophysiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ER alpha and ER beta) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ER alpha. KO mice display multiple significant defects in reproduction and mammarygland development, ER beta KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also demonstrated roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer. (C) 2015 Elsevier Ltd. All rights reserved.

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