STEROIDS A New Estrogenic Pathway

Although estrogens have classically been believed to act through nuclear receptors that function as transcription factors, it has become increasingly apparent that, as with other steroid hormones, rapid effects of estrogens can be initiated at the plasma membrane. The receptors and pathways through which these peripheral effects are mediated, however, remain unclear. Qiu et al. investigated modulation of -aminobutyric acid (GABA)-mediated activation of heterotrimeric guanosine triphosphate-binding protein-coupled inwardly rectifying K⁺ (GIRK) channels by 17ß-estradiol (E₂) in hypothalamic neurons. They identified a signaling pathway that involved activation of G_q after E₂ binding to a transmembrane estrogen receptor. The authors used whole-cell recordings of GABA-, proopiomelanocortin-, and dopamine-expressing neurons in hypothalamic slices from ovariectomized guinea pigs to investigate the effects of E₂ and various selective estrogen receptor modulators (SERMs) on GIRK activation by the GABA_B receptor agonist baclofen. E₂ inhibited baclofen-mediated GIRK activation, as did raloxifene, STX (a SERM without activity at nuclear estrogen receptors), and membrane-impermeant E₂ bound to bovine serum albumen, whereas tamoxifen did not. Pharmacological analysis indicated that this effect of E₂ involved protein kinase C acting upstream of protein kinase A, but not mitogen-activated protein kinase pathways. The authors used a peptide inhibitor to implicate G_q in this signaling pathway. These data extend the mechanisms whereby estrogens are known to act within the central nervous system; moreover, the identification of STX as selective for this pathway may facilitate the development of highly specific approaches to estrogen therapy.

J. Qiu, M. A. Bosch, S. C. Tobias, D. K. Grandy, T. S. Scanlan, O. K. Rønnekleiv, M. J. Kelly, Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J. Neurosci 23, 9529-9540 (2003). [Abstract] [Full Text]

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VIRTUAL JOURNAL
Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

Jian Qiu, Martha A. Bosch, Sandra C. Tobias, David K. Grandy, Thomas S. Scanlan, Oline K. Rønnekleiv, and Martin J. Kelly (22 October 2003)
J. Neurosci. 23 (29), 9529.
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