Inhibition of 17-beta-estradiol on neuronal excitability via enhancing GIRK1-mediated inwardly rectifying potassium currents and GIRK1 expression.
BACKGROUND
Catamenial epilepsy is a common central nervous system disease in female, which is influenced by the 17-β-estradiol (estrogen) level during the menstrual cycle. Low level (<0.05ng/ml) of estrogen normally accompanies with the perimenstrual classification of catamenial epilepsy, however, without clear mechanism. In previous studies, estrogen has been demonstrated to possess widely regulatory effects on potassium channels. Here, the effect of 17-β-estradiol on modulating inwardly rectifying K+(Kir) currents was investigated in cultured hippocampal neurons. The underlying mechanism was also detected.


METHODS
In this research, null-estrogen cultures and spaying animals were used to mimicked the low level estrogen condition in menstrual period. Patch clamp recordings, western blotting and pharmacological experiments were performed to detect the effects of estrogen receptors and the underlying mechanisms.


RESULTS
Compared to those neurons in normal medium (with 0.1ng/ml estrogen), null-estrogen cultures or neurons treated by estrogen receptor blocker (ICI 182,780) both had significant suppressed Kir currents. The expression level of G protein-gated inwardly rectifying K+channel subunit 1 (GIRK1) was significantly decreased in spaying animals. Furthermore, a GIRK channel inhibitor (TPQ) similarly suppressed the Kir currents. Lastly, estrogen deficiency, estrogen receptor blocker and GIRK channel inhibitor all promoted the epileptiform bursting activities in neurons, as a result of Kir current suppression.


CONCLUSIONS
Taken together, 17-β-estradiol, by the activation of estrogen receptors, is essential for the maintenance of Kir currents, and thus has an inhibitory effect on the epileptiform bursting activities in cultured hippocampal neurons, whereas GIRK1 is the major intermedial mediator. This research provides a new mechanism for the pathogenesis of catamenial epilepsy, particularly in the menstrual period and the early section of follicular phase.
Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Yuwen
Y
Zhang
Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 200437, China.
Yian
Y
Huang
Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Guoxiang
G
Wang
Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: wang.xin@zs-hospital.sh.cn.
Xin
X
Wang
Institutes of Brain Science, State Key Laboratory for Medical Neurobiology, Collaborative Innovation Center for Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: yunwang@fudan.edu.cn.
Yun
Y
Wang
D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010052:Ovariectomy; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D001514:Bee Venoms; D065171:Estrogen Receptor Antagonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D026941:Sodium Channel Blockers; D000077267:Fulvestrant; C029738:tertiapin; D013779:Tetrodotoxin; D004958:Estradiol
17-β-Estradiol; Catamenial epilepsy; Epileptiform bursting; GIRK1; Kir current