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 ...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 findings identify a potential new target for the treatment of mechanical pain.展开更多
针对传统电容式触摸芯片的采样信号易受外部噪声干扰而引发注入锁定的现象,设计了一种多频采样电路。该电路引入5条充电电流支路,实现多频采样功能,减小采样信号受注入锁定现象的影响,提高采样精度。同时,设计了一种DOM(Delta over the ...针对传统电容式触摸芯片的采样信号易受外部噪声干扰而引发注入锁定的现象,设计了一种多频采样电路。该电路引入5条充电电流支路,实现多频采样功能,减小采样信号受注入锁定现象的影响,提高采样精度。同时,设计了一种DOM(Delta over the Mean)算法对采样信号进行处理,以此监测触摸输入引脚的电容值变化。仿真结果表明,多频采样电路输出的采样信号受噪声干扰的计数值偏差仅为0.46%;FPGA验证表明DOM算法的计算精度为1×10^(-8),最大绝对误差不超过0.4%;该电路具有强抗干扰、高可靠性、高精度特性,可应用于各类电容式触摸芯片。展开更多
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)+2 种基金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)。
文摘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 findings identify a potential new target for the treatment of mechanical pain.
文摘针对传统电容式触摸芯片的采样信号易受外部噪声干扰而引发注入锁定的现象,设计了一种多频采样电路。该电路引入5条充电电流支路,实现多频采样功能,减小采样信号受注入锁定现象的影响,提高采样精度。同时,设计了一种DOM(Delta over the Mean)算法对采样信号进行处理,以此监测触摸输入引脚的电容值变化。仿真结果表明,多频采样电路输出的采样信号受噪声干扰的计数值偏差仅为0.46%;FPGA验证表明DOM算法的计算精度为1×10^(-8),最大绝对误差不超过0.4%;该电路具有强抗干扰、高可靠性、高精度特性,可应用于各类电容式触摸芯片。
