|Title||Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||Moutal A, Luo S, Largent-Milnes TM, Vanderah TW, Khanna R|
|Date Published||2019 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 Journal||Neurobiol Pain|
|PubMed Central ID||PMC6505708|
|Grant List||R01 AT009716 / AT / NCCIH NIH HHS / United States |
R01 DA042852 / DA / NIDA NIH HHS / United States
R01 NS098772 / NS / NINDS NIH HHS / United States
Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain.
Faculty Member Reference:
Tally Largent-Milnes, PhD
Todd Vanderah, PhD