Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases NaV1.7 currents and reverses experimental neuropathic pain

Pain
Liberty François-MoutalRajesh Khanna

Abstract

We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in the axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking of the voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate the biophysical nature of the interaction between CRMP2 and the SUMOylation machinery, and test the hypothesis that a rationally designed CRMP2 SUMOylation motif (CSM) peptide can interrupt E2 SUMO-conjugating enzyme Ubc9-dependent modification of CRMP2 leading to a similar suppression of NaV1.7 currents. Microscale thermophoresis and amplified luminescent proximity homogeneous alpha assay revealed a low micromolar binding affinity between CRMP2 and Ubc9. A heptamer peptide harboring CRMP2's SUMO motif, also bound with similar affinity to Ubc9, disrupted the CRMP2-Ubc9 interaction in a concentration-dependent manner. Importantly, incubation of a tat-conjugated cell-penetrating peptide (t-CSM) decreased sodium currents, predominantly NaV1.7, in a model neuronal cell line. Dialysis of t-CSM peptide reduced CRMP2 SUMOylation and blocked surface trafficking of NaV1.7 in rat sensory neurons. Fluorescence dye-based imaging i...Continue Reading

References

Jul 1, 1994·Journal of Neuroscience Methods·S R ChaplanT L Yaksh
Jan 2, 2001·The Journal of Biological Chemistry·M S RodriguezR T Hay
May 15, 2001·American Journal of Physiology. Cell Physiology·A DiarraJ Church
Jul 31, 2001·Nature Neuroscience·N InagakiK Kaibuchi
Mar 6, 2002·The Journal of Biological Chemistry·Donghai LinYuan Chen
Dec 1, 1976·Physiology & Behavior·T L Yaksh, T A Rudy
Sep 24, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Theodore R CumminsStephen G Waxman
Mar 1, 2005·Oncogene·Yin-Yuan MoWilliam T Beck
Apr 6, 2005·Molecular Cell·Ronald T Hay
Apr 12, 2005·Cell·Sindhu RajanSteve A N Goldstein
Dec 6, 2005·Developmental Cell·Karim NacerddineAnne Dejean
May 6, 2006·British Journal of Anaesthesia·J MarcilP Beaulieu
Jun 8, 2006·Journal of Molecular Histology·Stergios J Moschos, Yin-Yuan Mo
Jan 26, 2007·Journal of Neurochemistry·Pål StenmarkPetri Kursula
May 9, 2007·Nature·Stéphane MartinJeremy M Henley
Aug 8, 2007·Neurology·Stephen G Waxman
Nov 8, 2007·Nature Reviews. Neuroscience·Stéphane MartinJeremy M Henley
Feb 5, 2008·Bioorganic & Medicinal Chemistry Letters·Clare LondonJoseph L Duffy
Aug 30, 2008·Molecular Pharmacology·William A SchmalhoferBirgit T Priest
Feb 3, 2009·Advances in Genetics·Sulayman D Dib-HajjStephen G Waxman
Mar 7, 2009·The Journal of Antibiotics·Isao FukudaMinoru Yoshida
Jun 27, 2009·Annals of Neurology·Tanya Z FischerStephen G Waxman
Jan 1, 2008·Current Chemical Genomics·Richard M EglenMartina Bielefeld
May 14, 2010·The Biochemical Journal·Kevin A Wilkinson, Jeremy M Henley
May 17, 2011·Bioorganic & Medicinal Chemistry Letters·Sultan ChowdhuryJay A Cadieux
Aug 5, 2011·Assay and Drug Development Technologies·Moran Jerabek-WillemsenStefan Duhr
Oct 21, 2011·Nature·Corine BertolottoBrigitte Bressac-de Paillerets
Jan 18, 2012·Neurobiology of Disease·Matthew K BrittainNickolay Brustovetsky

❮ Previous
Next ❯

Citations

Feb 20, 2020·Expert Opinion on Investigational Drugs·Mikhail KushnarevNebojsa Nick Knezevic
Mar 28, 2019·Molecular Neurobiology·Aubin MoutalRajesh Khanna
Jul 4, 2019·Journal of Molecular Neuroscience : MN·Leilei Wang, Suzhen Ji
Aug 29, 2019·Molecular Brain·Agustin Garcia-CaballeroGerald W Zamponi
Nov 5, 2019·Channels·Aubin MoutalRajesh Khanna
Dec 20, 2018·Molecular Neurobiology·Jie YuRajesh Khanna
Jun 17, 2020·Journal of Neurochemistry·Jeremy M HenleyKevin A Wilkinson
Jan 31, 2019·Biochemical Pharmacology·Lindsey A ChewRajesh Khanna
Mar 13, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xu ChenYitao Qi
Jun 15, 2021·Frontiers in Molecular Neuroscience·Jiurong ChengJun Zhou
Jul 23, 2020·ACS Chemical Neuroscience·Rajesh KhannaMarcel Patek
Nov 11, 2021·Science Translational Medicine·Song CaiRajesh Khanna

❮ Previous
Next ❯

Related Concepts

Related Feeds

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.