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Membrane Estrogen Receptor- Interacts with Metabotropic Glutamate Receptor Type 1a to Mobilize Intracellular Calcium in Hypothalamic Astrocytes

Department of Neurobiology (J.K., O.R.H., G.B., J.O., P.M.), Laboratory of Neuroendocrinology and Brain Research Institute, and Department of Obstetrics and Gynecology (J.K.), David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095

Address all correspondence and requests for reprints to: Dr. Paul Micevych, Department of Neurobiology, David Geffen School of Medicine at University of California, Los Angeles, 10833 LeConte Avenue, 73-078 CHS, Los Angeles, California 90095-1763. E-mail: pmicevych{at}mednet.ucla.edu.

Estradiol, acting on a membrane-associated estrogen receptor- (mER), induces an increase in free cytoplasmic calcium concentration ([Ca²⁺]_i) needed for progesterone synthesis in hypothalamic astrocytes. To determine whether rapid estradiol signaling involves an interaction of mER with metabotropic glutamate receptor type 1a (mGluR1a), changes in [Ca²⁺]_i were monitored with the calcium indicator, Fluo-4 AM, in primary cultures of female postpubertal hypothalamic astrocytes. 17β-Estradiol over a range of 1 nM to 100 nM induced a maximal increase in [Ca²⁺]_i flux measured as a change in relative fluorescence [F Ca²⁺ = 615 ± 36 to 641 ± 47 relative fluorescent units (RFU)], whereas 0.1 nM of estradiol stimulated a moderate [Ca²⁺]_i increase (275 ± 16 RFU). The rapid estradiol-induced [Ca²⁺]_i flux was blocked with 1 µM of the estrogen receptor antagonist ICI 182,780 (635 ± 24 vs. 102 ± 11 RFU, P < 0.001) and 20 nMof the mGluR1a antagonist LY 367385 (617 ± 35 vs. 133 ± 20 RFU, P < 0.001). Whereas the mGluR1a receptor agonist (RS)-3,5-dihydroxyphenyl-glycine (50 µM) also stimulated a robust [Ca²⁺]_i flux (626 ± 23 RFU), combined treatment of estradiol (1 nM) plus (RS)-3,5-dihydroxyphenyl-glycine (50 µM) augmented the [Ca²⁺]_i response (762 ± 17 RFU) compared with either compound alone (P < 0.001). Coimmunoprecipitation demonstrated a direct physical interaction between mER and mGluR1a in the plasma membrane of hypothalamic astrocytes. These results indicate that mER acts through mGluR1a, and mGluR1a activation facilitates the estradiol response, suggesting that neural activity can modify estradiol-induced membrane signaling in astrocytes.

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