Calcineurin-mediated GABA(A) receptor dephosphorylation in rats after kainic acid-induced status epilepticus.
Calcineurin (CaN) is a neuronally enriched, calcium-dependent phosphatase, which plays an important role in a number of neuronal processes including development of learning and memory, and modulation of receptor's function and neuronal excitability as well as induction of apoptosis. It has been established in kindling model that the status epilepticus (SE)-induced increase in CaN activity is involved in the development of seizures through down-regulation of gamma-aminobutyric acid A receptor (GABA(A)R) activation. However, the mechanism by which CaN mediates GABA(A) receptor dephosphorylation in SE is not fully understood. Here, using a model of kainic acid (KA)-induced SE and CaN inhibitor FK506, we observed the behaviors induced by KA and levels of CaN activity and CaN expression in hippocampus by immunobloting. The results showed that the SE-induced CaN activity was time-dependent, with a peak at 2h and a return to basal level at 24h, whereas a significant increase in CaN expression was seen at 24h after SE. It is proposed that the rapid elevation in CaN activity after KA-induced SE is not likely due to an increase in CaN expression but rather an increase in CaN activation state or kinetics. In addition, we also demonstrated that pre-treatment with FK506 remarkably suppressed the SE-induced CaN activity and its expression, and reversed the SE-induced dephosphorylation of GABA(A)R 2/3 subunits. Taken together, our data suggest that down-regulation in inhibition of GABA(A)R 2/3 by CaN activity contributes to an elevation in neuronal excitability of hippocampus, which may be involved in development of chronic processes of seizures.
Wang
Aihua
A
Department of Neurology, Qianfoshan Hospital, Medical School of Shandong University, No. 66, Jingshi Road, Jinan, Shandong 250014, PR China. wangah_0052@sina.com
Chi
Zhaofu
Z
Wang
Shengjun
S
Wang
Shuhua
S
Sun
Qinjian
Q
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007608:Kainic Acid; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D013226:Status Epilepticus / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
D007166:Immunosuppressive Agents; D011963:Receptors, GABA-A; D019703:Calcineurin; D007608:Kainic Acid; D020123:Sirolimus; D016559:Tacrolimus