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Phosphorylated CRMP2 Regulates Spinal Nociceptive Neurotransmission

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Abstract

The collapsin response mediator protein 2 (CRMP2) has emerged as a central node in assembling nociceptive signaling complexes involving voltage-gated ion channels. Concerted actions of post-translational modifications, phosphorylation and SUMOylation, of CRMP2 contribute to regulation of pathological pain states. In the present study, we demonstrate a novel role for CRMP2 in spinal nociceptive transmission. We found that, of six possible post-translational modifications, three phosphorylation sites on CRMP2 were critical for regulating calcium influx in dorsal root ganglion sensory neurons. Of these, only CRMP2 phosphorylated at serine 522 by cyclin-dependent kinase 5 (Cdk5) contributed to spinal neurotransmission in a bidirectional manner. Accordingly, expression of a non-phosphorylatable CRMP2 (S522A) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), whereas expression of a constitutively phosphorylated CRMP2 (S522D) increased the frequency of sEPSCs. The presynaptic nature of CRMP2’s actions was further confirmed by pharmacological antagonism of Cdk5-mediated CRMP2 phosphorylation with S-N-benzy-2-acetamido-3-methoxypropionamide ((S)-lacosamide; (S)-LCM) which (i) decreased sEPSC frequency, (ii) increased paired-pulse ratio, and (iii) reduced the presynaptic distribution of CaV2.2 and NaV1.7, two voltage-gated ion channels implicated in nociceptive signaling. (S)-LCM also inhibited depolarization-evoked release of the pro-nociceptive neurotransmitter calcitonin gene-related peptide (CGRP) in the spinal cord. Increased CRMP2 phosphorylation in rats with spared nerve injury (SNI) was decreased by intrathecal administration of (S)-LCM resulting in a loss of presynaptic localization of CaV2.2 and NaV1.7. Together, these findings indicate that CRMP2 regulates presynaptic excitatory neurotransmission in spinal cord and may play an important role in regulating pathological pain. Novel targeting strategies to inhibit CRMP2 phosphorylation by Cdk5 may have great potential for the treatment of chronic pain.

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Funding

This work was supported by a grant from the National Natural Science Foundation of China (81603088) to J.Y., a grant from the National Institutes of Health to JMW (R01NS082283), National Institutes of Health awards (R01NS098772 from the National Institute of Neurological Disorders and Stroke and R01DA042852 from the National Institute on Drug Abuse to R.K.), and a Neurofibromatosis New Investigator Award from the Department of Defense Congressionally Directed Military Medical Research and Development Program (NF1000099) to R.K. S.S.B. and N.Y.N.P. were supported by funds to the Undergraduate Biology Research Program from the University of Arizona’s Senior Vice President for Research’s office, and the University of Arizona’s Native American Cancer Prevention Program (N.Y.N.P.).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA

    Jie Yu, Aubin Moutal, Angie Dorame, Shreya S. Bellampalli, Aude Chefdeville, Iori Kanazawa, Nancy Y. N. Pham & Rajesh Khanna

  2. College of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310058, China

    Jie Yu

  3. Korea Institute of Science and Technology, Seoul, South Korea

    Ki Duk Park

  4. Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA

    Jill M. Weimer

  5. Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine, Vermillion, SD, USA

    Jill M. Weimer

  6. Department of Pediatrics, University of South Dakota, Sioux Falls, SD, USA

    Jill M. Weimer

  7. The Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, AZ, 85724, USA

    Rajesh Khanna

Authors
  1. Jie Yu
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  2. Aubin Moutal
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  3. Angie Dorame
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  4. Shreya S. Bellampalli
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  5. Aude Chefdeville
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  6. Iori Kanazawa
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  7. Nancy Y. N. Pham
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  8. Ki Duk Park
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  9. Jill M. Weimer
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  10. Rajesh Khanna
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Corresponding author

Correspondence to Rajesh Khanna.

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Jie Yu and Aubin Moutal are co-first authors.

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Yu, J., Moutal, A., Dorame, A. et al. Phosphorylated CRMP2 Regulates Spinal Nociceptive Neurotransmission. Mol Neurobiol 56, 5241–5255 (2019). https://doi.org/10.1007/s12035-018-1445-6

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  • DOI: https://doi.org/10.1007/s12035-018-1445-6

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