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.

CONCLUSION

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.