Nonclassical Estrogen Modulation of Presynaptic GABA Terminals Modulates Calcium Dynamics in Gonadotropin-Releasing Hormone Neurons

Endocrinology. 2008 Nov;149(11):5335-44. doi: 10.1210/en.2008-0424. Epub 2008 Aug 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Calcium / metabolism
  • Calcium Signaling / drug effects*
  • Calcium Signaling / genetics
  • Dose-Response Relationship, Drug
  • Estradiol / metabolism
  • Estradiol / pharmacology*
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Estrogen Receptor beta / physiology
  • Gonadotropin-Releasing Hormone / genetics
  • Gonadotropin-Releasing Hormone / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Knockout
  • Models, Biological
  • Neurons / drug effects*
  • Neurons / metabolism
  • Presynaptic Terminals / drug effects*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics
  • Time Factors
  • Transcription, Genetic / drug effects
  • gamma-Aminobutyric Acid / metabolism*


  • Estrogen Receptor beta
  • Gonadotropin-Releasing Hormone
  • Estradiol
  • gamma-Aminobutyric Acid
  • Calcium