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Regulation of Cyclic Adenosine 3',5'-Monophosphate Signaling and Pulsatile Neurosecretion by G_i-coupled Plasma Membrane Estrogen Receptors in Immortalized Gonadotropin-Releasing Hormone Neurons

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510

Address all correspondence and requests for reprints to: Kevin J. Catt, M.D., Ph.D., Endocrinology and Reproduction Research Branch, Building 49, Room 6A-36, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. E-mail: catt{at}helix.nih.gov.

Immortalized GnRH neurons (GT1–7) express receptors for estrogen [estrogen receptor- and -ß(ER and ERß)] and progesterone (progesterone receptor A) and exhibit positive immunostaining for both intracellular and plasma membrane ERs. Exposure of GT1–7 cells to picomolar estradiol concentrations for 5–60 min caused rapid, sustained, and dose-dependent inhibition of cAMP production. In contrast, treatment with nanomolar estradiol concentrations for 60 min increased cAMP production. The inhibitory and stimulatory actions of estradiol on cAMP formation were abolished by the ER antagonist, ICI 182,780. The estradiol-induced inhibition of cAMP production was prevented by treatment with pertussis toxin, consistent with coupling of the plasma membrane ER to an inhibitory G protein. Coimmunoprecipitation studies demonstrated an estradiol-regulated stimulatory interaction between ER and G_i3 that was prevented by the ER antagonist, ICI 182,780. Exposure of perifused GT1–7 cells and hypothalamic neurons to picomolar estradiol levels increased the GnRH peak interval, shortened peak duration, and increased peak amplitude. These findings indicate that occupancy of the plasma membrane-associated ERs expressed in GT1–7 neurons by physiological estradiol levels causes activation of a G_i protein and modulates cAMP signaling and neuropeptide secretion.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  PR

Ligands:   17β-Estradiol  |  Progesterone

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