Estrogens directly potentiate neuronal L-type Ca2+ channels.
L-type voltage-gated Ca(2+)channels (VGCC) play an important role in dendritic development, neuronal survival, and synaptic plasticity. Recent studies have demonstrated that the gonadal steroid estrogen rapidly induces Ca(2+) influx in hippocampal neurons, which is required for neuroprotection and potentiation of LTP. The mechanism by which estrogen rapidly induces this Ca(2+) influx is not clearly understood. We show by electrophysiological studies that extremely low concentrations of estrogens acutely potentiate VGCC in hippocampal neurons, hippocampal slices, and HEK-293 cells transfected with neuronal L-type VGCC, in a manner that was estrogen receptor (ER)-independent. Equilibrium, competitive, and whole-cell binding assays indicate that estrogen directly interacts with the VGCC. Furthermore, a L-type VGCC antagonist to the dihydropyridine site displaced estrogen binding to neuronal membranes, and the effects of estrogen were markedly attenuated in a mutant, dihydropyridine-insensitive L-type VGCC, demonstrating a direct interaction of estrogens with L-type VGCC. Thus, estrogen-induced potentiation of calcium influx via L-type VGCC may link electrical events with rapid intracellular signaling seen with estrogen exposure leading to modulation of synaptic plasticity, neuroprotection, and memory formation.
Sarkar
Saumyendra N
SN
Department of Pharmacology and Neuroscience and the Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. ssarkar@hsc.unt.edu
Huang
Ren-Qi
RQ
Logan
Shaun M
SM
Yi
Kun Don
KD
Dillon
Glenn H
GH
Simpkins
James W
JW
D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D020746:Calcium Channels, L-Type; D004967:Estrogens; C419385:L-type calcium channel alpha(1C); D011960:Receptors, Estrogen; D011994:Recombinant Proteins; D004958:Estradiol