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Int. J. Mol. Sci. 2014, 15(6), 10892-10907; doi:10.3390/ijms150610892
Article

Activation of mGluR5 Attenuates NMDA-Induced Neurotoxicity through Disruption of the NMDAR-PSD-95 Complex and Preservation of Mitochondrial Function in Differentiated PC12 Cells

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Received: 17 April 2014; in revised form: 16 May 2014 / Accepted: 30 May 2014 / Published: 17 June 2014
(This article belongs to the collection G Protein-Coupled Receptor Signaling and Regulation)
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Abstract: 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.
Keywords: glutamate; mGlu receptor; NMDAR (N-methyl-d-aspartate receptor) receptor; post-synaptic density protein 95; mitochondrial dysfunction glutamate; mGlu receptor; NMDAR (N-methyl-d-aspartate receptor) receptor; post-synaptic density protein 95; mitochondrial dysfunction
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Dai, S.-H.; Qin, N.; Chen, T.; Luo, P.; Zhang, L.; Rao, W.; Yang, Y.-F.; Jiang, X.-F.; Fei, Z. Activation of mGluR5 Attenuates NMDA-Induced Neurotoxicity through Disruption of the NMDAR-PSD-95 Complex and Preservation of Mitochondrial Function in Differentiated PC12 Cells. Int. J. Mol. Sci. 2014, 15, 10892-10907.

AMA Style

Dai S-H, Qin N, Chen T, Luo P, Zhang L, Rao W, Yang Y-F, Jiang X-F, Fei Z. Activation of mGluR5 Attenuates NMDA-Induced Neurotoxicity through Disruption of the NMDAR-PSD-95 Complex and Preservation of Mitochondrial Function in Differentiated PC12 Cells. International Journal of Molecular Sciences. 2014; 15(6):10892-10907.

Chicago/Turabian Style

Dai, Shu-Hui; Qin, Na; Chen, Tao; Luo, Peng; Zhang, Lei; Rao, Wei; Yang, Yue-Fan; Jiang, Xiao-Fan; Fei, Zhou. 2014. "Activation of mGluR5 Attenuates NMDA-Induced Neurotoxicity through Disruption of the NMDAR-PSD-95 Complex and Preservation of Mitochondrial Function in Differentiated PC12 Cells." Int. J. Mol. Sci. 15, no. 6: 10892-10907.



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