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Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain

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Abstract

Phosphorylation of N-methyl-d-aspartate receptor (NMDAR) is widely regarded as a vital modification of synaptic function. Various protein kinases are responsible for direct phosphorylation of NMDAR, such as cyclic adenosine monophosphate-dependent protein kinase A, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, Src family protein tyrosine kinases, cyclin-dependent kinase 5, and casein kinase II. The detailed function of these kinases on distinct subunits of NMDAR has been reported previously and contributes to phosphorylation at sites predominately within the C-terminal of NMDAR. Phosphorylation underlies both structural and functional changes observed in chronic pain, and studies have demonstrated that inhibitors of kinases are significantly effective in alleviating pain behavior in different chronic pain models. In addition, the exploration of drugs that aim to disrupt the interaction between kinases and NMDAR is promising in clinical research. Based on research regarding the modulation of NMDAR in chronic pain models, this review provides an overview of the phosphorylation of NMDAR-related mechanisms underlying chronic pain to elucidate molecular and pharmacologic references for chronic pain management.

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Data Availability

We did not use any data in the review, and all the materials were collected from the published literature resources.

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Acknowledgements

We are grateful to all the researchers who make contributions to all the studies involved in this review, and everyone who offers helpful comments and revises to this work.

Funding

This work was supported by the National Natural Science Foundation of China under contract (Grant Nos. 82071250, 31672290), Advanced Interdisciplinary Program of College of Advanced Interdisciplinary Studies (Grant No. JC18-03), Innovation and entrepreneurship education reform research project of Central South University (Grant No. 2019CG052), Postgraduate Education Reform Project of Central South University (Grant No. 2021JGB105), Biochemistry Maker Space of Central South University (Grant No. 2015CK009).

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  1. Department of Biochemistry and Molecular Biology and Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha, 410013, Hunan, China

    Liangyu Pan, Tiansheng Li, Rui Wang, Weiheng Deng & Meichun Deng

  2. College of Advanced Interdisciplinary Studies, National University of Defense Technology, Changsha, 410073, Hunan, China

    Huangsheng Pu

  3. Hunan Key Laboratory of Animal Models for Human Diseases & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410013, Hunan, China

    Liangyu Pan, Tiansheng Li, Rui Wang, Weiheng Deng & Meichun Deng

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LP designed and wrote the manuscript, and prepared the figures and table. TL, RW, and WD wrote the manuscript and prepared the figure. MD designed and supervised the work.

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Pan, L., Li, T., Wang, R. et al. Roles of Phosphorylation of N-Methyl-d-Aspartate Receptor in Chronic Pain. Cell Mol Neurobiol 43, 155–175 (2023). https://doi.org/10.1007/s10571-022-01188-6

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