Review
Rapid actions of plasma membrane estrogen receptors

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Abstract

Functional evidence for the existence of plasma membrane estrogen receptors in a variety of cell types continues to accumulate. Many of these functions originate from rapid signaling events, transduced in response to 17β-estradiol (E2). It has been convincingly shown that E2 activates phosphoinositol 3-kinase and protein kinase B/AKT, and stimulates ERK and p38 MAP kinases. In part, this stems from G-protein activation and the resulting calcium flux. As a result, the link between E2 action at the cell membrane and discrete biological actions in the cell has been strengthened. There is now convincing in vitro evidence that E2 can modulate the functions of neural and vascular cells via non-genomic actions. Thus, the actions of discrete pools of E2 receptors are likely to contribute to the overall effects of the sex steroids.

Section snippets

E2 modulates Ca2+ flux and generates cyclic nucleotides via membrane receptors

In a variety of cell types, numerous investigations continue to support the ability of a membrane ER to regulate Ca2+ flux. This regulation occurs (after seconds to a few minutes) in response to E2 exposure. E2 can rapidly stimulate the entry of Ca2+ into isolated duodenal enterocytes through a phospholipase C (PLC)-dependent mechanism involving store-operated Ca2+ channels 10. The effects are specific, in that they are not seen with progesterone (P4) or testosterone (T). These results are

Effects of E2 on membrane channels in the central nervous system

The effects of E2 on the hypothalamus and anterior pituitary act in concert with its effects on other tissues (e.g. ovary, uterus) to ensure a single ovulatory event that is precisely timed. In the 1970s, it was found that hypothalamic neurons were rapidly (within seconds) inhibited by inotophoretically applied E2 (Refs 24, 25, 26). Subsequently, it was shown that E2-mediated hyperpolarization of hypothalamic gonadotropin-releasing hormone (GnRH) and amygdala neurons is caused by the opening of

Effects of E2 on membrane channels in peripheral excitable cells

Pharmacological concentrations of E2 can rapidly inhibit L-type Ca2+ currents and shorten the action potential duration in guinea pig ventricular and atrial myocytes 36, 37. Micromolar concentrations of E2 inhibit 80% of the L-type Ca2+ current in isolated myocytes. These acute effects of E2 are reversible and are mimicked by diethylstilbesterol (a synthetic estrogen) and ethinyl estradiol, but not by testosterone or progesterone 37. Nakajima and colleagues 37, using GTPβS in whole-cell patch

Additional mechanisms of signaling by a membrane ER

In a variety of target cells, E2 serves as both a growth and a survival factor. In breast cancer, E2 can inhibit the cytotoxicity of chemotherapy, a process that occurs mainly by apoptotic cell death 45. This appears to be regulated, in part, through synthesis of the antiapoptotic protein, Bcl2. Ultraviolet irradiation or the chemotherapeutic agent taxol depend upon the activation of c-Jun N-terminal kinase (JNK) to enact apoptosis in several cell types 46, 47. E2 significantly blocks the

Membrane localization of the plasma membrane ER

In GH 3/B6 pituitary tumor cells, E2 rapidly induces the intracellular release of Ca2+ and the influx of Ca2+ through voltage-gated Ca2+ channels before prolactin secretion 56, 57. Based on confocal laser microscopy of the binding of E2–BSA, studies using selective antibodies to ERα (e.g. H222) and the binding of ERα antagonists, the membrane receptor in these pituitary cells appears to be ERα or an isoform of this receptor.

However, in the CNS, on the basis of electrophysiological experiments

Perspective

It appears that E2 can interact with distinct, compartmentalized pools of receptors, each having unique effects on cellular physiology. In this way, the cell can accomplish either rapid modifications of protein action (via signaling through membrane ERα, ERβ or another ER), or more prolonged regulation of cell protein synthesis and function (via the actions of the nuclear receptors). As a consequence, rapid and more prolonged steroid hormone action could be exquisitely coordinated. However, it

Acknowledgements

Work in the authors’ laboratories was supported by PHS grants NS 38809, DA 05158 and DA 00192 (RSDA) to MJK, and HL59890 to ERL, and by grants from the Dept of Veterans Affairs and the Dept of Defense to ERL.

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