TY - JOUR
T1 - Studies on CRMP2 SUMOylation–deficient transgenic mice identify sex-specific Nav1.7 regulation in the pathogenesis of chronic neuropathic pain
AU - Moutal, Aubin
AU - Cai, Song
AU - Yu, Jie
AU - Stratton, Harrison J.
AU - Chefdeville, Aude
AU - Gomez, Kimberly
AU - Ran, Dongzhi
AU - Madura, Cynthia L.
AU - Boinon, Lisa
AU - Soto, Maira
AU - Zhou, Yuan
AU - Shan, Zhiming
AU - Chew, Lindsey A.
AU - Rodgers, Kathleen E.
AU - Khanna, Rajesh
N1 - Publisher Copyright:
© 2020 International Association for the Study of Pain.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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 (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. By contrast, in a neuropathic model, CRMP2K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation–dependent control of peripheral Na 1.7 is a hallmark of chronic but not physiological neuropathic pain.
AB - 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 (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. By contrast, in a neuropathic model, CRMP2K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation–dependent control of peripheral Na 1.7 is a hallmark of chronic but not physiological neuropathic pain.
KW - CRMP2
KW - Na1.7
KW - SUMOylation
KW - neuropathic pain
KW - sex specific
KW - trafficking
UR - http://www.scopus.com/inward/record.url?scp=85093706209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093706209&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000001951
DO - 10.1097/j.pain.0000000000001951
M3 - Article
C2 - 32569093
AN - SCOPUS:85093706209
SN - 0304-3959
VL - 161
SP - 2629
EP - 2651
JO - Pain
JF - Pain
IS - 11
ER -