FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2

Abstract Background FSC231, a PSD‐95/DLG/ZO‐1 (PDZ) domain inhibitor of protein kinase Cα interacting protein 1 (PICK1), has analgesic effects, but the mechanism remains unclear. Methods The expression level of PICK1 in dorsal root ganglion (DRG) of rats was changed by vector plasmid, and the effect...

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Autores principales:	Xi Zhang, Jiagao Wang, Ran Ran, Yuchuan Peng, Yun Xiao
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	FSC231 GluA2 GSK‐3β paclitaxel PICK1 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/4868e715503d4de28112596ba3d4548e
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spelling	oai:doaj.org-article:4868e715503d4de28112596ba3d4548e2021-11-25T06:06:36ZFSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/22162-327910.1002/brb3.2380https://doaj.org/article/4868e715503d4de28112596ba3d4548e2021-11-01T00:00:00Zhttps://doi.org/10.1002/brb3.2380https://doaj.org/toc/2162-3279Abstract Background FSC231, a PSD‐95/DLG/ZO‐1 (PDZ) domain inhibitor of protein kinase Cα interacting protein 1 (PICK1), has analgesic effects, but the mechanism remains unclear. Methods The expression level of PICK1 in dorsal root ganglion (DRG) of rats was changed by vector plasmid, and the effect of PICK1 on paclitaxel (PTL)‐induced neuralgia of rats was observed in collaboration with FSC231 treatment. The possible molecular mechanisms were explored by quantitative real‐time polymerase chain reaction (qRT‐PCR), Western Blot and co‐immunoprecipitation (Co‐IP) techniques. Results PTL treatment can significantly reduce mechanical withdrawal threshold (MWT), shorten thermal withdrawal latency (TWL), promote DRG inflammation and release of substance P (SP), stimulate PICK1 expression, decrease α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor 2 (AMPAR, GluA2) level and increase glycogen synthase kinase‐3β (GSK‐3β) and extracellular regulated protein kinases1/2 (ERK1/2) phosphorylation in rats, while FSC231 treatment can alleviate the above effects induced by PTL. Overexpression of PICK1 can counteract reduced PICK1 level, increased GluA2 level and decreased GSK‐3β and ERK1/2 phosphorylation levels caused by FSC231 treatment. The results of Co‐IP confirmed the interactions between PICK1 and GluA2. Both FSC231 treatment and silent PICK1 improved PTL‐induced MWT reduction, TWL shortening, inflammation, SP release and related gene expression changes, with cumulative effect. Conclusion FSC231 activates GSK‐3β/ERK1/2 by inhibiting the interaction between PICK1 and GluA2 and alleviates PTL‐induced DRG neuralgia in rats.Xi ZhangJiagao WangRan RanYuchuan PengYun XiaoWileyarticleFSC231GluA2GSK‐3βpaclitaxelPICK1Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENBrain and Behavior, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FSC231 GluA2 GSK‐3β paclitaxel PICK1 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	FSC231 GluA2 GSK‐3β paclitaxel PICK1 Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Xi Zhang Jiagao Wang Ran Ran Yuchuan Peng Yun Xiao FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
description	Abstract Background FSC231, a PSD‐95/DLG/ZO‐1 (PDZ) domain inhibitor of protein kinase Cα interacting protein 1 (PICK1), has analgesic effects, but the mechanism remains unclear. Methods The expression level of PICK1 in dorsal root ganglion (DRG) of rats was changed by vector plasmid, and the effect of PICK1 on paclitaxel (PTL)‐induced neuralgia of rats was observed in collaboration with FSC231 treatment. The possible molecular mechanisms were explored by quantitative real‐time polymerase chain reaction (qRT‐PCR), Western Blot and co‐immunoprecipitation (Co‐IP) techniques. Results PTL treatment can significantly reduce mechanical withdrawal threshold (MWT), shorten thermal withdrawal latency (TWL), promote DRG inflammation and release of substance P (SP), stimulate PICK1 expression, decrease α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor 2 (AMPAR, GluA2) level and increase glycogen synthase kinase‐3β (GSK‐3β) and extracellular regulated protein kinases1/2 (ERK1/2) phosphorylation in rats, while FSC231 treatment can alleviate the above effects induced by PTL. Overexpression of PICK1 can counteract reduced PICK1 level, increased GluA2 level and decreased GSK‐3β and ERK1/2 phosphorylation levels caused by FSC231 treatment. The results of Co‐IP confirmed the interactions between PICK1 and GluA2. Both FSC231 treatment and silent PICK1 improved PTL‐induced MWT reduction, TWL shortening, inflammation, SP release and related gene expression changes, with cumulative effect. Conclusion FSC231 activates GSK‐3β/ERK1/2 by inhibiting the interaction between PICK1 and GluA2 and alleviates PTL‐induced DRG neuralgia in rats.
format	article
author	Xi Zhang Jiagao Wang Ran Ran Yuchuan Peng Yun Xiao
author_facet	Xi Zhang Jiagao Wang Ran Ran Yuchuan Peng Yun Xiao
author_sort	Xi Zhang
title	FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
title_short	FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
title_full	FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
title_fullStr	FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
title_full_unstemmed	FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2
title_sort	fsc231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between pick1 and glua2 and activates gsk‐3β and erk1/2
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/4868e715503d4de28112596ba3d4548e
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FSC231 alleviates paclitaxel‐induced neuralgia by inhibiting the interactions between PICK1 and GluA2 and activates GSK‐3β and ERK1/2

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