Regulation of GluR6-PSD95-MLK3 Signaling in KA-Induced Epilepsy

Abstract

Glutamate receptors are classified into two groups: metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs). The ionotropic glutamate receptors are superfamily of ligand-gated cation channels that encompass three receptor families identified by the agonists that selectively activate them: N-methyl-D-aspartate (NMDA), αamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and kainic acid (KA) receptors (Dingledine et al. 1999, Mayer & Armstrong 2004, Kew & Kemp 2005). KA is a potent exogenous agonist of KA receptors and AMPA receptors, and systemic administration of KA produces epilepsy in rats and mice accompanied by neuronal damage mainly in limbic structures. In particular, hippocampal pyramidal neurons are highly vulnerable to the excitotoxicity of KA (Sperk et al. 1983). KA-induced seizures in rodents have been widely used as a model of human temporal lobe epilepsy on the basis of both behavioral and pathological similarities (Ben-Ari 1985). KA receptors are comprised of five different subunits: KA1, KA2, GluR5, GluR6 and GluR7 (Lilliu et al. 2002, Porter et al. 1997). It is reported that GluR6 subunit-deficient and Jnk3 gene knock-out mice resistance to KA-induced seizures and neuronal toxicity (Yang et al. 1997, Mulle et al. 1998). And the Glur6 midiated JNK3 (c-Jun N-terminal kinase 3) signaling pathway has been pay more attention in the study of neuron damage during epilepsia. C terminus of GluR6 can bind to the PDZ1 domain of the postsynaptic density protein PSD95/SAP90 through specific interaction (Garcia et al. 1998, Mehta et al. 2001). Previous studies have also shown that MLK3 (mixed lineage kinase-3), an upstream kinase of JNK (Tibbles et al. 1996), can interact with the SH3 (Src homology) domain of PSD95 (Savinainen et al. 2001). The triple complex GluR6-PSD95-MLK3 may exist and facilitate JNK activation. In our previous studies on brain ischemia, it has demonstrated that KA enhanced the assembly of GluR6-PSD95-MLK3 module, increased the autophosphorylation of MLK3 and the phosphorylation of MKK7 (mitogen-activated protein kinase kinase 7), JNK3, c-Jun and Bcl-2 (B-cell lymphoma 2), raised the expression of Fas-Ligand (FasL) and caused the release of Bax (Bcl-2 associated x protein) from Bcl-2/Bax dimmers and the release of cytochrome c from mitochondria (Pei et al. 2006). Consequently, the activation of Caspase 3 led to delayed neuronal death in the hippocampal CA1/CA3 subfield (Tian et al. 2005, Pei et al. 2005, Pan et al. 2005). The activation of mitochondrion-linked apoptotic signaling pathways after seizures, including activation of caspase-9, -3, and -8, has also been reported (Henshall et al. 2000). And we further found that KA-induced neuronal death is mediated by the GluR6-