Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking  

作　　者：Man-Xiu Xie Ren-Chun Lai Yi-Bin Xiao Xi Zhang Xian-Ying Cao Xiao-Yu Tian An-Nan Chen Zi-Yi Chen Yan Cao Xiao Li Xiao-Long Zhang 

机构地区：[1]Department of Anesthesiology,Sun Yat-Sen University Cancer Center,State Key Laboratory of Oncology in South China,Guangdong Provincial Clinical Research Center for Cancer,Guangzhou,510060,China [2]Medical Research Institute,Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangzhou,510080,China [3]Pain Research Center and Department of Physiology,Zhongshan School of Medicine of Sun Yat-Sen University,Guangzhou,510080,China [4]Engineering Technology Research Center for Elderly Health Management in Hainan Province,Haikou,571137,China [5]College of Food Science and Technology,Hainan University,Haikou,570228,China

出　　处：《Military Medical Research》2025年第2期157-183,共27页军事医学研究(英文版)

基　　金：National Natural Science Foundation of China(82271241 and 82001172 to XLZ,81801112 to MXX);Guangdong Basic and Applied Basic Research Foundation(2022A1515012389 to MXX,2022A1515012543 to RCL);Young Talent Support Project of Guangzhou Association for Science and Technology(QT20220101169 to XLZ);Excellent Young Talents Project of Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences(KY012021188 to XLZ);Science and Technology Projects in Guangzhou(202201010792 to RCL)。

摘　　要：Background Tactile and mechanical pain are crucial to our interaction with the environment,yet the underpinning molecular mechanism is still elusive.Endophilin A2(EndoA2)is an evolutionarily conserved protein that is documented in the endocytosis pathway.However,the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear.Methods Male and female C57BL/6 mice(8–12 weeks)and male cynomolgus monkeys(7–10 years old)were used in our experiments.Nerve injury-,inflammatory-,and chemotherapy-induced pathological pain models were established for this study.Behavioral tests of touch,mechanical pain,heat pain,and cold pain were performed in mice and nonhuman primates.Western blotting,immunostaining,co-immunoprecipitation,proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms.Results The results showed that EndoA2 was primarily distributed in neurofilament-200-positive(NF200+)medium-to-large diameter dorsal root ganglion(DRG)neurons of mice and humans.Loss of EndoA2 in mouse NF200+DRG neurons selectively impaired the tactile and mechanical allodynia.Furthermore,EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons.Moreover,as an adaptor protein,EndoA2 also bound to kinesin family member 5B(KIF5B),which was involved in the EndoA2-mediated membrane trafficking process of Piezo2.Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents,and re-expression of EndoA2 rescued the MA currents.In addition,interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates.Conclusions Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals.EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons.Our finding

关 键 词：Endophilin A2 TOUCH Mechanical allodynia Piezo2 KIF5B 

分 类 号：R402[医药卫生—临床医学]