Regulation of cyclic adenosine 3',5'-monophosphate signaling and pulsatile neurosecretion by Gi-coupled plasma membrane estrogen receptors in immortalized gonadotropin-releasing hormone neurons.
Immortalized GnRH neurons (GT1-7) express receptors for estrogen [estrogen receptor-alpha and -beta(ERalpha and ERbeta)] 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 ERalpha and Galphai3 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 Gi protein and modulates cAMP signaling and neuropeptide secretion.
Navarro
Carlos E
CE
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abdul Saeed
Sheikh
S
Murdock
Cynthia
C
Martinez-Fuentes
Antonio J
AJ
Arora
Krishan K
KK
Krsmanovic
Lazar Z
LZ
Catt
Kevin J
KJ
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism*; D009489:Neurosecretion / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000242:Cyclic AMP