title: Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure.
abstract: 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.
authors.affiliation: Research Center of Biochemistry and Molecular Biology, Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Xu
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Wang
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Yu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhu
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Yu
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Pei
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: 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
chemical_list: 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