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.
Sun
Jianli
J
Departments of Medicine and Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
Chu
Zhiguo
Z
Moenter
Suzanne M
SM
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