Diurnal in vivo and rapid in vitro effects of estradiol on voltage-gated calcium channels in gonadotropin-releasing hormone neurons.
A robust surge of gonadotropin-releasing hormone (GnRH) release triggers the luteinizing hormone surge that induces ovulation. The GnRH surge is attributable to estradiol feedback, but the mechanisms are incompletely understood. Voltage-gated calcium channels (VGCCs) regulate hormone release and neuronal excitability, and may be part of the surge-generating mechanism. We examined VGCCs of GnRH neurons in brain slices from a model exhibiting daily luteinizing hormone surges. Mice were ovariectomized (OVX), and a subset was treated with estradiol implants (OVX+E). OVX+E mice exhibit negative feedback in the A.M. and positive feedback in the P.M. GnRH neurons express prominent high-voltage-activated (HVA) and small low-voltage-activated (LVA) macroscopic (whole-cell) Ca currents (I(Ca)). LVA-mediated currents were not altered by estradiol or time of day. In contrast, in OVX+E mice, HVA-mediated currents varied with time of day; HVA currents in cells from OVX+E mice were lower than those in cells from OVX mice in the A.M. but were higher in the P.M. These changes were attributable to diurnal alternations in L- and N-type components. There were no diurnal changes in any aspect of HVA-mediated I(Ca) in OVX mice. Acute in vitro treatment of cells from OVX and OVX+E mice with estradiol rapidly increased HVA currents primarily through L- and R-type VGCCs by activating estrogen receptor beta and GPR30, respectively. These results suggest multiple mechanisms contribute to the overall feedback regulation of HVA-mediated I(Ca) by estradiol. In combination with changes in synaptic inputs to GnRH neurons, these intrinsic changes in GnRH neurons may play critical roles in estradiol feedback.
Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
Jianli
J
Sun
Zhiguo
Z
Chu
Suzanne M
SM
Moenter
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004343:Drug Implants / Q000008:administration & dosage / Q000494:pharmacology; D004958:Estradiol / Q000008:administration & dosage* / Q000502:physiology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004343:Drug Implants; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol