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Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases Na(V)1.7 currents and reverses experimental neuropathic pain 期刊论文

编号：

bbee2a7c-175b-4b42-ad9e-64fe6be78038
作者：

FrancoisMoutal, Liberty#^[1]Dustrude, Erik T.^[1];Wang, Yue^[1];Brustovetsky, Tatiana^[2];Dorame, Angie^[1];Ju, Weina(鞠维娜)^[3,4]Moutal, Aubin^[1];PerezMiller, Samantha^[1];Brustovetsky, Nickolay^[2];Gokhale, Vijay^[5];Khanna, May^[1,6];Khanna, Rajesh*^[1,6,7]
语种：

英文
期刊：

PAIN ISSN：0304-3959 2018 年 159 卷 10 期 (2115 - 2127) ; OCT
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关键词：

Na(V)1.7 CRMP2 SUMOylation motif decoy Neuropathic pain
摘要：

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 Na(V)1.7 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 Na(V)1.7 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 Na(V)1.7, in a model neuronal cell line. Dialysis of t-CSM peptide reduced CRMP2 SUMOylation and blocked surface trafficking of Na(V)1.7 in rat sensory neurons. Fluorescence dye-based imaging in rat sensory neurons demonstrated inhibition of sodium influx in the presence of t-CSM peptide; by contrast, calcium influx was unaffected. Finally, t-CSM effectively reversed persistent mechanical and thermal hypersensitivity induced by a spinal nerve injury, a model of neuropathic pain. Structural modeling has now identified a pocket-harboring CRMP2's SUMOylation motif that, when targeted through computational screening of ligands/molecules, is expected to identify small molecules that will biochemically and functionally target CRMP2's SUMOylation to reduce NaV1.7 currents and reverse neuropathic pain.
推荐引用方式
GB/T 7714：

Francois-Moutal Liberty,Dustrude Erik T.,Wang Yue, et al. Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases Na(V)1.7 currents and reverses experimental neuropathic pain [J].PAIN,2018,159(10):2115-2127.
APA：

Francois-Moutal Liberty,Dustrude Erik T.,Wang Yue,Brustovetsky Tatiana,&Khanna Rajesh.(2018).Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases Na(V)1.7 currents and reverses experimental neuropathic pain .PAIN,159(10):2115-2127.
MLA：

Francois-Moutal Liberty, et al. "Inhibition of the Ubc9 E2 SUMO-conjugating enzyme-CRMP2 interaction decreases Na(V)1.7 currents and reverses experimental neuropathic pain" .PAIN 159,10(2018):2115-2127.
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