RT Journal Article
SR Electronic
T1 Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific NaV1.7 regulation in the pathogenesis of chronic neuropathic pain
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.20.049106
DO 10.1101/2020.04.20.049106
A1 Aubin Moutal
A1 Song Cai
A1 Jie Yu
A1 Harrison J. Stratton
A1 Aude Chefdeville
A1 Kimberly Gomez
A1 Dongzhi Ran
A1 Cynthia L. Madura
A1 Lisa Boinon
A1 Maira Soto
A1 Yuan Zhou
A1 Zhiming Shan
A1 Lindsey A. Chew
A1 Kathleen E. Rodgers
A1 Rajesh Khanna
YR 2020
UL http://biorxiv.org/content/early/2020/04/21/2020.04.20.049106.abstract
AB The sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a “poster child” for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2K374A/K374A) mice in which Lys374 was replaced with Ala. CRMP2K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain.Competing Interest StatementR. Khanna is the co-founder of Regulonix LLC, a company developing non-opioids drugs for chronic pain. In addition, R. Khanna has patents US10287334 and US10441586 issued to Regulonix LLC. The other authors declare no competing financial interest.