Editorial [Hot Topic: GPR30/GPER vs. ERalpha and ERbeta: Why Estrogens Need so Many Receptors (Guest Editor: Marcello Maggiolini)]

Estrogens regulate numerous physiological functions through two well-characterized members of the nuclear receptor superfamily, the estrogen receptors (ER)α and ERβ. In recent years, numerous studies have shown that the G protein-coupled receptor 30 (GPR30, also named GPER) mediates rapid responses to estrogens and even ER antagonists in diverse normal and cancer cell types. The GPER-activated signaling is clearly distinct from that of the classical nuclear ERs, however the transduction pathways triggered by GPER and ERs interact in some cases and cooperatively regulate relevant biological functions. In addition to various investigations which focused on GPER-mediated action in cancer, several reports have also been performed in order to uncover the role exerted by GPER in the reproductive organs, the bone, the cardiovascular, nervous and immunological systems. In this respect, new pharmacological tools as agonist/antagonist compounds have been identified and used to dissect and differentiate the peculiar GPER-dependent signaling. Overall, an increasing number of reports have provided novel insight toward a better understanding of the estrogen action elicited through many receptors which engage in an intricate transduction network involved in both physiological and pathological cell responses. Certainly, the discovery of GPER has opened a remarkable debate in the scientific community encouraging new efforts in order to further assess the multifaceted estrogen routes. This review highlights the ability of GPER in mediating the estrogen signals in diverse cell types and tissues, hence contributing to the current questions regarding its function as an alternate estrogen receptor.