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Review
, 176, 73-81

GPER Modulators: Opportunity Nox on the Heels of a Class Akt

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Review

GPER Modulators: Opportunity Nox on the Heels of a Class Akt

Eric R Prossnitz. J Steroid Biochem Mol Biol.

Abstract

The (patho)physiology of estrogen and its receptors is complex. It is therefore not surprising that therapeutic approaches targeting this hormone include stimulation of its activity through supplementation with either the hormone itself or natural or synthetic agonists, inhibition of its activity through the use of antagonists or inhibitors of its synthesis, and tissue-selective modulation of its activity with biased ligands. The physiology of this hormone is further complicated by the existence of at least three receptors, the classical nuclear estrogen receptors α and β (ERα and ERβ), and the 7-transmembrane G protein-coupled estrogen receptor (GPER/GPR30), with overlapping but distinct pharmacologic profiles, particularly of anti-estrogenic ligands. GPER-selective ligands, as well as GPER knockout mice, have greatly aided our understanding of the physiological roles of GPER. Such ligands have revealed that GPER activation mediates many of the rapid cellular signaling events (including Ca2+ mobilization, ERK and PI3K/Akt activation) associated with estrogen activity, as opposed to the nuclear ERs that are traditionally described to function as ligand-induced transcriptional factors. Many of the salutary effects of estrogen throughout the body are reproduced by the GPER-selective agonist G-1, which, owing to its minimal effects on reproductive tissues, can be considered a non-feminizing estrogenic compound, and thus of potential therapeutic use in both women and men. On the contrary, until recently GPER-selective antagonists had predominantly found preclinical application in cancer models where estrogen stimulates cell growth and survival. This viewpoint changed recently with the discovery that GPER is associated with aging, particularly that of the cardiovascular system, where the GPER antagonist G36 reduced hypertension and GPER deficiency prevented cardiac fibrosis and vascular dysfunction with age, through the downregulation of Nox1 and as a consequence superoxide production. Thus, similar to the classical ERs, both agonists and antagonists of GPER may be of therapeutic benefit depending on the disease or condition to be treated.

Keywords: Cancer; Diabetes; Estrogen; GPER; Inflammation; Multiple sclerosis; Obesity; Vascular.

Conflict of interest statement

Competing interests: E.R.P. is an inventor on a U.S. patent application for the therapeutic use of compounds targeting GPER and on U.S. patent Nos. 7,875,721 and 8,487,100 for GPER-selective ligands and imaging agents.

Figures

Figure 1
Figure 1
Structures of GPER-selective compounds. Chemical structures of GPER-selective agonist G-1 and GPER-selective antagonists G15 and G36.
Figure 2
Figure 2
Salutary effects of GPER modulation by both agonism and antagonism. Stimulation of GPER activity with the selective agonist G-1 leads to the activation of multiple signaling pathways, including that of Akt, that have been shown to lead to therapeutic benefit in a number of disease models. In the cardiovascular system, many of the salutary effects of GPER stimulation appear to be mediated through the Akt-mediated activation of eNOS, leading to generation of nitric oxide (NO). Alternatively, antagonism of GPER with selective antagonists, such as G36, leads to the downregulation of Nox1 protein, which results in lower levels of superoxide (•O2). This chronic reduction in reactive oxygen species leads to salutary effects, for example in the cardiovascular system, in part through reductions in blood pressure and fibrogenesis.

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