Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion.
In this study, we investigated whether the increase of inhibitory gamma-amino butyric acid (GABA) signal suppresses the excitatory glutamate signal induced by cerebral ischemia and the underlying mechanisms. In global cerebral ischemia, focal cerebral ischemia and oxygen-glucose deprivation, application of muscimol and baclofen, agonists of GABA(A) receptor and GABA(B) receptor, exerted neuroprotection. The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade. Our results suggest that stimulation 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 in cerebral ischemia.
Han
Dong
D
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, People's Republic of China.
Zhang
Quan-Guang
QG
Yong-Liu
Li
Chong
C
Zong
Yan-Yan
YY
Yu
Chang-Zhou
CZ
Wang
Wei
W
Yan
Jing-Zhi
JZ
Zhang
Guang-Yi
GY
D000818:Animals; D017209:Apoptosis; D001418:Baclofen / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D018755:GABA Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors*; D009118:Muscimol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D015398:Signal Transduction; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor
D001418:Baclofen; D000076122:Disks Large Homolog 4 Protein; D018755:GABA Agonists; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D048057:Mitogen-Activated Protein Kinase 10; D009118:Muscimol; D018079:Receptors, GABA; D018092:Kainic Acid Receptors; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor; C501449:Dlg4 protein, rat