PMID- 24941251 OWN - NLM STAT- MEDLINE DCOM- 20150127 LR - 20211021 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 15 IP - 6 DP - 2014 Jun 17 TI - Activation of mGluR5 attenuates NMDA-induced neurotoxicity through disruption of the NMDAR-PSD-95 complex and preservation of mitochondrial function in differentiated PC12 cells. PG - 10892-907 LID - 10.3390/ijms150610892 [doi] AB - Glutamate-mediated toxicity is implicated in various neuropathologic conditions, and activation of ionotropic and metabotropic glutamate receptors is considered to be the most important mechanism. It has been reported that pharmacological saturation of metabotropic glutamate receptors (mGluRs) can facilitate N-methyl-D-aspartate receptor (NMDAR) related signaling cascades, but the mechanism leading to mGluR-NMDAR interactions in excitotoxic neuronal injury has remained unidentified. In the present study, we investigated the role of mGluR5 in the regulation of N-methyl-D-aspartate (NMDA)-induced excitotoxicity in differentiated PC12 cells. We found that activation of mGluR5 with the specific agonist R,S-2-chloro-5-hydroxyphenylglycine (CHPG) increased cell viability and inhibited lactate dehydrogenase (LDH) release in a dose-dependent manner. CHPG also inhibited an increase in the Bax/Bcl-2 ratio, attenuated cleavage of caspase-9 and caspase-3, and reduced apoptotic cell death after NMDA treatment. The NMDA-induced mitochondrial dysfunction, as indicated by mitochondrial reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential (MMP), and cytochrome c release, was also partly prevented by CHPG treatment. Furthermore, CHPG blocked the NMDA-induced interaction of NMDAR with postsynaptic density protein-95 (PSD-95), but had no effects on intracellular calcium concentrations. All these results indicated that activation of mGluR5 protects differentiated PC12 cells from NMDA-induced neuronal excitotoxicity by disrupting NMDAR-PSD-95 interaction, which might be an ideal target for investigating therapeutic strategies in various neurological diseases where excitotoxicity may contribute to their pathology. FAU - Dai, Shu-Hui AU - Dai SH AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmudaishuhui@163.com. FAU - Qin, Na AU - Qin N AD - Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuqinna@163.com. FAU - Chen, Tao AU - Chen T AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuchentao@163.com. FAU - Luo, Peng AU - Luo P AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuluopeng@163.com. FAU - Zhang, Lei AU - Zhang L AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuzhanglei@163.com. FAU - Rao, Wei AU - Rao W AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuraowei@163.com. FAU - Yang, Yue-Fan AU - Yang YF AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmuyangyf@126.com. FAU - Jiang, Xiao-Fan AU - Jiang XF AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. fmmujiangxiaofan@163.com. FAU - Fei, Zhou AU - Fei Z AD - Department of Neurosurgery, Xijing Institute of Clinical Neuroscience, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. zhoufei@fmmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140617 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (2-chloro-5-hydroxyphenylglycine) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, rat) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Membrane Proteins) RN - 0 (Phenylacetates) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptor, Metabotropic Glutamate 5) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 6384-92-5 (N-Methylaspartate) RN - 9007-43-6 (Cytochromes c) RN - SY7Q814VUP (Calcium) RN - TE7660XO1C (Glycine) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Calcium/metabolism MH - Cell Differentiation/drug effects MH - Cell Survival/drug effects MH - Cytochromes c/metabolism MH - Disks Large Homolog 4 Protein MH - Glycine/analogs & derivatives/pharmacology MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - Membrane Potential, Mitochondrial/drug effects MH - Membrane Proteins/*metabolism MH - Mitochondria/*metabolism MH - N-Methylaspartate/toxicity MH - PC12 Cells MH - Phenylacetates/pharmacology MH - Protein Binding MH - Rats MH - Reactive Oxygen Species/metabolism MH - Receptor, Metabotropic Glutamate 5/agonists/*metabolism MH - Receptors, N-Methyl-D-Aspartate/*metabolism MH - Stereoisomerism PMC - PMC4100187 EDAT- 2014/06/19 06:00 MHDA- 2015/01/28 06:00 PMCR- 2014/06/01 CRDT- 2014/06/19 06:00 PHST- 2014/04/17 00:00 [received] PHST- 2014/05/16 00:00 [revised] PHST- 2014/05/30 00:00 [accepted] PHST- 2014/06/19 06:00 [entrez] PHST- 2014/06/19 06:00 [pubmed] PHST- 2015/01/28 06:00 [medline] PHST- 2014/06/01 00:00 [pmc-release] AID - ijms150610892 [pii] AID - ijms-15-10892 [pii] AID - 10.3390/ijms150610892 [doi] PST - epublish SO - Int J Mol Sci. 2014 Jun 17;15(6):10892-907. doi: 10.3390/ijms150610892.