Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific Nav1.7 regulation in the pathogenesis of chronic neuropathic pain.

Autor:	Moutal A; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Cai S; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Yu J; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Stratton HJ; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Chefdeville A; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Gomez K; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Ran D; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Madura CL; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Boinon L; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Soto M; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States.; Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, United States., Zhou Y; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Shan Z; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Chew LA; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States., Rodgers KE; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States.; Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, United States., Khanna R; Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ, United States. Dr. Chew is now with the Duke University School of Medicine, Durham, NC, United States.; Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ, United States.; BIO5 Institute, University of Arizona, Tucson, AZ, United States.; Department of Anesthesiology, College of Medicine, The University of Arizona, Tucson, AZ, United States.
Jazyk:	angličtina
Zdroj:	Pain [Pain] 2020 Nov; Vol. 161 (11), pp. 2629-2651.
DOI:	10.1097/j.pain.0000000000001951
Abstrakt:	The sodium channel Nav1.7 is a master regulator of nociceptive input into the central nervous system. Mutations in this channel can result in painful conditions and 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. Among 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 (CRMP2) mice in which Lys374 was replaced with Ala. CRMP2 mice had reduced Nav1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 mice to inflammatory, acute, or visceral pain. By contrast, in a neuropathic model, CRMP2 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu