Voltage-gated sodium channels(VGSCs) are transmembrane proteins responsible for generation and conduction of action potentials in excitable cells.Physiological and pharmacological studies have demonstrated that VGSCs ...Voltage-gated sodium channels(VGSCs) are transmembrane proteins responsible for generation and conduction of action potentials in excitable cells.Physiological and pharmacological studies have demonstrated that VGSCs play a critical role in chronic pain associated with tissue or nerve injury.Many long-chain peptide toxins(60-76 amino acid residues) purified from the venom of Asian scorpion Buthus martensii Karsch(BmK) are investigated to be sodium channel-specific modulators.The α-like neurotoxins that can bind to receptor site 3 of sodium channels,named as BmK I and BmK abT,could induce nociceptive effects in rats.On the contrast,the β-like neurotoxins that can bind to receptor site 4 of sodium channels,named as BmK AS,BmK AS-1 and BmK IT2,could produce potent anti-nociceptive effects in animal pain models.BmK I could strongly prolong the fast inactivation of tetrodotoxin(TTX)-sensitive Na+ currents on the rat dorsal root ganglia(DRG) neurons together with the augmentation of peak current amplitude.However,BmK IT2 and BmK ASs,potently suppressed both the peak TTX-resistant and TTX-sensitive Na+ currents on rat small DRG neurons.Moreover,BmK ASs could decrease the excitability of small DRG neurons.Thus,the nociception/anti-nociception induced by scorpion neurotoxins may attribute to their distinct modulation on sodium channels in primary afferent sensory neurons.Therefore,the sodium channel-specific modulators from BmK venom could be used as not only pharmacological tools for better understanding the roles of VGSCs in pain signal conduction,but also lead molecules in the development of ideal analgesics targeting VGSCs.展开更多
雷帕霉素(Rapamycin,Rap)是一种免疫抑制剂,在临床上主要应用于器官移植过程中的抗排异反应,同时,Rap在抗癌、神经保护和抗衰老等领域也展现出巨大潜力。通过抑制哺乳动物Rap靶蛋白(mammalian target of Rapamycin,mTOR)活性,Rap能够活...雷帕霉素(Rapamycin,Rap)是一种免疫抑制剂,在临床上主要应用于器官移植过程中的抗排异反应,同时,Rap在抗癌、神经保护和抗衰老等领域也展现出巨大潜力。通过抑制哺乳动物Rap靶蛋白(mammalian target of Rapamycin,mTOR)活性,Rap能够活化调节溶酶体功能的转录因子EB(transcription factor EB,TFEB)从而上调溶酶体功能,同时,Rap也能够去除mTOR对ULK1(unc-51 like autophagy activating kinase 1)的抑制效果从而促进自噬。最新研究显示,Rap能够直接激活溶酶体钙离子通道TRPML1,此效应并不依赖于mTOR;TRPML1通道的开放可释放溶酶体钙离子,钙调神经磷酸酶(Calcineurin)作为此溶酶体来源的钙信号的感受器活化TFEB,进而增强溶酶体功能并促进自噬。此发现拓宽了对Rap药理学机制的认知,为衰老等领域的机制研究提供了理论基础。本文将以经典的Rap-mTOR-ULK1/TFEB信号通路为导引,详细介绍溶酶体钙离子通道TRPML1被确认为Rap新靶标的论证过程,并简要讨论此新信号通路(Rap-TRPML1-Calcineurin-TFEB)的药理学意义。展开更多
基金grants from National Basic Research Development Program of China(No.2006CB500801)National Natural Sciences Foundation of China(No.30370446)
文摘Voltage-gated sodium channels(VGSCs) are transmembrane proteins responsible for generation and conduction of action potentials in excitable cells.Physiological and pharmacological studies have demonstrated that VGSCs play a critical role in chronic pain associated with tissue or nerve injury.Many long-chain peptide toxins(60-76 amino acid residues) purified from the venom of Asian scorpion Buthus martensii Karsch(BmK) are investigated to be sodium channel-specific modulators.The α-like neurotoxins that can bind to receptor site 3 of sodium channels,named as BmK I and BmK abT,could induce nociceptive effects in rats.On the contrast,the β-like neurotoxins that can bind to receptor site 4 of sodium channels,named as BmK AS,BmK AS-1 and BmK IT2,could produce potent anti-nociceptive effects in animal pain models.BmK I could strongly prolong the fast inactivation of tetrodotoxin(TTX)-sensitive Na+ currents on the rat dorsal root ganglia(DRG) neurons together with the augmentation of peak current amplitude.However,BmK IT2 and BmK ASs,potently suppressed both the peak TTX-resistant and TTX-sensitive Na+ currents on rat small DRG neurons.Moreover,BmK ASs could decrease the excitability of small DRG neurons.Thus,the nociception/anti-nociception induced by scorpion neurotoxins may attribute to their distinct modulation on sodium channels in primary afferent sensory neurons.Therefore,the sodium channel-specific modulators from BmK venom could be used as not only pharmacological tools for better understanding the roles of VGSCs in pain signal conduction,but also lead molecules in the development of ideal analgesics targeting VGSCs.
基金Supported by the National Natural Science Foundation of China （50874107） the Guizhou Science and Technology Fund （Qiankehe J zi [2012]2306）+1 种基金 the Guizhou High-level Talent Special Assistant Fund （TZJF-2011-04） the Guizhou Research Laboratory Platform of Clean and Efficient Use of Coal Resources （Qianke Platform [2011] 4003）
基金grants from the National Natural Science Foundation of China(No.82074162,81903995)the Young Elite Scientists Sponsorship Program by CACM(No.CACM-2019-QNRC2-C10)+1 种基金Science and Technology Innovation Project of Putuo District Health System(No.ptkwws201902,ptkwws201908,ptkwws202009,ptkwws202107)and Research Project(No.2019307,2020308A)the One Hundred Talents(No.2022-RCLH-02)of Putuo Hospital,Shanghai University of Traditional Chinese Medicine。
基金supported by the National Natural Science Foundation of China (No. 81572859)National Basic Research Development Program of China (No. 2014CB910303)+5 种基金Scientific Fund of Shanghai Commission of Health and Family Planning (No. 201640201 201740027 and 201840003)the Scientific Program of District of Chongming Science and Technology Committee Shanghai Municipality China (No. CKY2016-03 CKZ2015-01 and CKY2018-3)
