mGluR5 positive modulators both potentiate activation and restore inhibition in NMDA receptors by PKC dependent pathway

Journal of Biomedical Science

Research

Hwei-Hsien Chen¹  Pei-Fei Liao¹  Ming-Huan Chan¹ 

[1] Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan;

关键词: NMDA Receptor;    Hippocampal Slice;    NMDA Receptor Antagonist;    NMDA Receptor Activation;    Ifenprodil;   

DOI  :  10.1186/1423-0127-18-19

 received in 2010-09-15, accepted in 2011-02-22,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundIn order to understand the interaction between the metabotropic glutamate subtype 5 (mGluR5) and N-methyl-D-aspartate (NMDA) receptors, the influence of mGluR5 positive modulators in the inhibition of NMDA receptors by the noncompetitive antagonist ketamine, the competitive antagonist D-APV and the selective NR2B inhibitor ifenprodil was investigated.MethodsThis study used the multi-electrode dish (MED) system to observe field potentials in hippocampal slices of mice.ResultsData showed that the mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as the positive allosteric modulators 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) and 3,3'-difluorobenzaldazine (DFB) alone did not alter the basal field potentials, but enhanced the amplitude of field potentials induced by NMDA. The inhibitory action of ketamine on NMDA-induced response was reversed by CHPG, DFB, and CDPPB, whereas the blockade of NMDA receptor by D-APV was restored by CHPG and CDPPB, but not by DFB. Alternatively, activation of NMDA receptors prior to the application of mGluR5 modulators, CHPG was able to enhance NMDA-induced field potentials and reverse the suppressive effect of ketamine and D-APV, but not ifenprodil. In addition, chelerythrine chloride (CTC), a protein kinase C (PKC) inhibitor, blocked the regulation of mGluR5 positive modulators in enhancing NMDA receptor activation and recovering NMDA receptor inhibition. The PKC activator (PMA) mimicked the effects of mGluR5 positive modulators on enhancing NMDA receptor activation and reversing NMDA antagonist-evoked NMDA receptor suppression.ConclusionOur results demonstrate that the PKC-dependent pathway may be involved in the positive modulation of mGluR5 resulting in potentiating NMDA receptor activation and reversing NMDA receptor suppression induced by NMDA antagonists.

【 授权许可】

Unknown   
© Chen et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.