Nonclassical estrogen modulation of presynaptic GABA terminals modulates calcium dynamics in gonadotropin-releasing hormone neurons.
There is increasing recognition that estrogen exerts multifaceted regulatory effects on GnRH neurons. The acute effects of estrogen on calcium dynamics in these cells were examined using a transgenic mouse line that allows real-time measurement of intracellular calcium concentration ([Ca2+]i) in GnRH neurons in the acute brain slice preparation. 17-beta-Estradiol (E2) at 100 pm-100 nm was found to activate [Ca2+]i transients in approximately 40% of GnRH neurons with an approximate 15-min latency. This effect was not replicated by E2-BSA, which limits E2 action to the membrane, 17-alpha-estradiol, the inactive isomer at classical estrogen receptors (ERs), or G-1 the GPR30 agonist. E2 continued to activate [Ca2+]i transients when transcription was blocked. An ER alpha-selective agonist was equally potent in activating [Ca2+]i transients, and E2 remained effective in ERbeta knockout x GnRH-Pericam mice. E2's activation of [Ca2+]i transients continued in the presence of tetrodotoxin, which blocks action potential-dependent transmission, but was abolished completely by the further addition of a gamma-aminobutyric acid (GABA)A receptor antagonist. Exogenous GABA was found to initiate [Ca2+]i transients in GnRH neurons. Whole cell, voltage-clamp recordings of GnRH-green fluorescence protein neurons revealed that E2 generated discrete bursts of miniature inhibitory postsynaptic currents with a latency of approximately 15 min. These observations provide evidence for a new mechanism of nonclassical estrogen action within the brain. Estrogen interacts with the classical ERalpha at the level of the GABAergic nerve terminal to regulate action potential-independent GABA release that, in turn, controls postsynaptic calcium dynamics.
Romanò
Nicola
N
Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin, New Zealand.
Lee
Kiho
K
Abrahám
István M
IM
Jasoni
Christine L
CL
Herbison
Allan E
AE
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D047629:Estrogen Receptor beta; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D005680:gamma-Aminobutyric Acid; D002118:Calcium