Trends in Endocrinology & Metabolism
ReviewRapid actions of plasma membrane estrogen receptors
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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