Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain.

TitleCdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain.
Publication TypeJournal Article
Year of Publication2019
AuthorsMoutal A, Luo S, Largent-Milnes TM, Vanderah TW, Khanna R
JournalNeurobiol Pain
Date Published2019 Jan-Jul

Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain.

Alternate JournalNeurobiol Pain
PubMed ID31080913
PubMed Central IDPMC6505708
Grant ListR01 AT009716 / AT / NCCIH NIH HHS / United States
R01 DA042852 / DA / NIDA NIH HHS / United States
R01 NS098772 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, PhD
Todd Vanderah, PhD