Co-activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6-PSD95-MLK3 signaling module in cerebral ischemic-reperfusion

Edited by Jesus Avila

Received 6 December 2007; received in revised form 19 January 2008; accepted 18 February 2008. published online 26 February 2008.

Abstract

In this study, we investigated whether the increase of inhibitory γ-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.

Abbreviations: NMDA, N-methyl-d-aspartic acid, GABA, γ-amino butyric acid

Keywords: Cerebral ischemia, Muscimol, Baclofen, JNK pathway, Neuroprotection

Research Center for Biochemistry and Molecular Biology, Provincial Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou, Jiangsu 221002, PR China

Corresponding author. Fax: +86 516 8574 8486.

1 These authors contribute equally to this work.

PII: S0014-5793(08)00155-5

doi:10.1016/j.febslet.2008.02.044

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