Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure.
OBJECTIVE
Past work has demonstrated that kainic acid (KA)-induced seizures could cause the enhancement of excitation and lead to neuronal death in rat hippocampus. To counteract such an imbalance between excitation and inhibition, we designed experiments by activating the inhibitory gamma-aminobutyric acid (GABA) receptor to investigate whether such activation suppresses the excitatory glutamate signaling induced by KA and to elucidate the underlying molecular mechanisms.


METHODS
Muscimol coapplied with baclofen was intraperitoneally administrated to the rats 40 min before KA injection by intracerebroventricular infusion. Subsequently we used a series of methods including immunoprecipitation, immunoblotting, histologic analysis, and immunohistochemistry to analyze the interaction, expression, and phosphorylation of relevant proteins as well as the survival of the CA1/CA3 pyramidal neurons.


RESULTS
Coadministration of muscimol and baclofen exerted neuroprotection against neuron death induced by KA; inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by KA; and suppressed the activation of MLK3, MKK7, and JNK3.


CONCLUSIONS
Taken together, we demonstrate that coactivation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module induced by KA. This provides a new insight into the therapeutic approach to epileptic seizure.
Li
Chong
C
Research Center of Biochemistry and Molecular Biology, Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu, China.
Xu
Bo
B
Wang
Wei-Wei
WW
Yu
Xiu-Ju
XJ
Zhu
Jie
J
Yu
Hong-Min
HM
Han
Dong
D
Pei
Dong-Sheng
DS
Zhang
Guang-Yi
GY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001418:Baclofen / Q000494:pharmacology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018755:GABA Agonists / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D007608:Kainic Acid / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D009118:Muscimol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects; D018092:Kainic Acid Receptors / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor
D001418:Baclofen; D000076122:Disks Large Homolog 4 Protein; D018755:GABA Agonists; D047908:Intracellular Signaling Peptides and Proteins; D007608:Kainic Acid; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D048057:Mitogen-Activated Protein Kinase 10; D009118:Muscimol; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C501449:Dlg4 protein, rat