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(S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5

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Abstract

The neuronal circuit remodels during development as well as in human neuropathologies such as epilepsy. Neurite outgrowth is an obligatory step in these events. We recently reported that alterations in the phosphorylation state of an axon specification/guidance protein, the collapsin response mediator protein 2 (CRMP2), play a major role in the activity-dependent regulation of neurite outgrowth. We also identified (S)-LCM, an inactive stereoisomer of the clinically used antiepileptic drug (R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. Here, we investigated the mechanism by which (S)-LCM affects CRMP2 phosphorylation by two key kinases, cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK-3β). (S)-LCM application to embryonic cortical neurons resulted in reduced levels of Cdk5- and GSK-3β-phosphorylated CRMP2. Mechanistically, (S)-LCM increased CRMP2 binding to both Cdk5- and GSK-3β without affecting binding of CRMP2 to its canonical partner tubulin. Saturation transfer difference nuclear magnetic resonance (STD NMR) and differential scanning fluorimetry (DSF) experiments demonstrated direct binding of (S)-LCM to CRMP2. Using an in vitro luminescent kinase assay, we observed that (S)-LCM specifically inhibited Cdk5-mediated phosphorylation of CRMP2. Cross-linking experiments and analytical ultracentrifugation showed no effect of (S)-LCM on the oligomerization state of CRMP2. The increased association between Cdk5-phosphorylated CRMP2 and CaV2.2 was reduced by (S)-LCM in vitro and in vivo. This reduction translated into a decrease of calcium influx via CaV2.2 in (S)-LCM-treated neurons compared to controls. (S)-LCM, to our knowledge, is the first molecule described to directly inhibit CRMP2 phosphorylation and may be useful for delineating CRMP2-facilitated functions.

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Acknowledgments

This work was supported by a Korea Institute of Science and Technology (KIST) institutional program grant 2E25240 to K.D.P., a Career Development Award from the Arizona Health Science Center to M.K., a National Scientist Development grant SDG5280023 from the American Heart Association, and a Neurofibromatosis New Investigator Award NF1000099 from the Department of Defense Congressionally Directed Military Medical Research and Development Program to R.K. We thank Dr. Harold Kohn for providing (S)-Lacosamide, Dr. Karl J. Dria (Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis) for mass spectrometry analysis of purified CRMP2, and Dr. Chad K. Park (Analytical Biophysics Facility, Department of Chemistry and Biochemistry, University of Arizona) for analytical density ultracentrifugation. We also thank Marissa Posada and Daniel J. Carlson for technical assistance, Erik T. Dustrude and Dr. Nickolay Brustovetsky (Indiana University School of Medicine) and Dr. Sarah M. Wilson for helpful comments on the manuscript.

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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, 85742, USA

    Aubin Moutal, Liberty François-Moutal, Samantha Perez-Miller, Karissa Cottier, Lindsey Anne Chew, May Khanna & Rajesh Khanna

  2. Neuroscience Graduate Interdisciplinary Program, College of Medicine, University of Arizona, Tucson, AZ, 85742, USA

    Rajesh Khanna

  3. Nuclear Magnetic Resonance Facility, Department of Chemistry and Biochemistry, College of Medicine, University of Arizona, Tucson, AZ, 85742, USA

    Jixun Dai

  4. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, Republic of Korea

    Seul Ki Yeon & Ki Duk Park

Authors
  1. Aubin Moutal
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  2. Liberty François-Moutal
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  3. Samantha Perez-Miller
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  4. Karissa Cottier
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  5. Lindsey Anne Chew
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  6. Seul Ki Yeon
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  7. Jixun Dai
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  8. Ki Duk Park
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  9. May Khanna
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  10. Rajesh Khanna
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Corresponding authors

Correspondence to May Khanna or Rajesh Khanna.

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Moutal, A., François-Moutal, L., Perez-Miller, S. et al. (S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5. Mol Neurobiol 53, 1959–1976 (2016). https://doi.org/10.1007/s12035-015-9141-2

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  • DOI: https://doi.org/10.1007/s12035-015-9141-2

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