Direct action of estradiol on gonadotropin-releasing hormone-1 neuronal activity via a transcription-dependent mechanism.
Pulsatile secretion of gonadotropin-releasing hormone-1 (GnRH-1) is essential for reproduction. GnRH-1 induces gonadotropin release and is regulated by 17beta-estradiol (E2). Although a subpopulation of GnRH-1 neurons expresses estrogen receptor (ER) beta, it is unclear whether E2 acts directly on GnRH-1 neurons or indirectly through interneuronal connections. To test the hypothesis that E2 acts directly on GnRH-1 neurons to regulate neuronal activity, we used calcium imaging to monitor intracellular calcium oscillations in GnRH-1 neurons maintained in nasal explants. TTX was used to minimize synaptic input from other cells. Consistent with previous studies, TTX reduced the activity of individual GnRH-1 neurons to a basal level, while the population of cells maintained synchronized calcium oscillations. Exposure of GnRH-1 cells to TTX plus E2 increased the number of calcium peaks/cell, percentage of cells with > or =10 peaks, mean peak amplitude, and percentage of cells that contributed to each calcium pulse in explants maintained in vitro for 7 d (7 div) compared with TTX alone. These effects were induced within 30 min and were not mimicked by 17alpha-estradiol, E2 conjugated to BSA (which does not cross the plasma membrane), or seen at 21 div, when the percentage of GnRH-1 cells expressing ERbeta transcripts declines. In addition, these effects were inhibited by the ER antagonist ICI 182,780 and prevented by inhibition of gene transcription. These data suggest that, via ERbeta, E2 can rapidly act as a hormone-activated transcription complex and are the first to show that E2 directly increases GnRH-1 neuronal activity and synchronization.
Temple
Jennifer L
JL
Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Laing
Eric
E
Sunder
Anushka
A
Wray
Susan
S
D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002118:Calcium / Q000032:analysis; D020013:Calcium Signaling; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000187:drug effects; D005260:Female; D005456:Fluorescent Dyes / Q000032:analysis; D000077267:Fulvestrant; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009297:Nasal Mucosa / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D009930:Organic Chemicals; D012636:Secretory Rate; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D020847:Estrogen Receptor Modulators; D047629:Estrogen Receptor beta; D005456:Fluorescent Dyes; D009930:Organic Chemicals; D026941:Sodium Channel Blockers; C071336:calcium green; D000077267:Fulvestrant; D007987:Gonadotropin-Releasing Hormone; D013779:Tetrodotoxin; D004958:Estradiol; D002118:Calcium