Characterization of α-conotoxin TxIB and TxID for smoking cessation and drug rehabilitation  

作　　者：ZHANGSUN Dong-ting ZHU Xiao-peng ZHANGSUN Man-qi WU Yong LI Xiao-dan Sean CHRISTENSEN Quentin KAAS Peta J HARVEY David J CRAIK J Michael MCINTOSH LUO Su-lan 

机构地区：[1]Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Lab for Marine Drug of Haikou, Hainan University, Haikou,570228, China [2]Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112, USA [3]Instit

出　　处：《中国药理学与毒理学杂志》2018年第9期711-713,共3页Chinese Journal of Pharmacology and Toxicology

摘　　要：Nicotinic acetylcholine receptors(nAChRs) are widely distributed ligand gated ion channels throughout the peripheral and central nervous systems of mammals.There are 16 different n AChR subunits,α1-α7,α9,α10 and β1-β4,as well as γ,δ,and ε,which assemble into pentamers to form different nAChR subtypes with distinct pharmacological properties in mammals.Among them α6β2*(*designates other possible subunit),α3β4 and α4β2 nAChR subtypes are potential therapeutic targets for the treatment of addiction.However,various n AChR subtypes are very difficult to pharmacologically distinguish from each other.The α6* n AChRs are expressed by dopaminergic neurons in the central nervous system,which modulate the release of dopamine and are believed to be important in mediating tobacco,morphine,cocaine and ethanol addiction.The α3β4 nAChRs present in the medial habenula with important role in influencing nicotine addiction.Blockage of α3β4 nAChRs in the medial habenula decreased the dose of nicotine that rodents would self-administer.Thus,new antagonists of α6β2* or α3β4 nA ChR subtypes are of considerable interest,which would give strategies to selectively modulate α6β2* or α3β4 nA ChR function.We characterized an α-conotoxin(α-CTx)TxIB with 16 amino acids and an α-CTx TxID with 15 amino acids from Conus textile.The sequence of TxIB is GCCSDPPCRNKHPDLCamide.The sequence of TxID is GCCSHPVCSAMSPIC with C-terminal amidation too.Both peptides with a Ⅰ-Ⅲ and Ⅱ-Ⅳ disulfide con-nectivity were chemically synthesized.The residues between Cys-Ⅱ and Cys-Ⅲ and Cys-Ⅲand Cys-Ⅳ of α-CTx are commonly referred to as loops 1 and 2,respectively.The number of residues in each of these loops is used to further classify the α-CTx.So TxIB is classified as a 4/7α-CTx,whereas the α-CTx TxIB has a 4/6 spacing.Both peptides were tested on rat nAChRs heterologously expressed in Xenopus laevis oocytes.The α-CTx TxIB blocked α6/α3β2β3 nAChR with an IC50 of 28 nmol·L^(-1),which showed little or no block Nicotinic acetylcholine receptors(nAChRs) are widely distributed ligand gated ion channels throughout the peripheral and central nervous systems of mammals.There are 16 different n AChR subunits,α1-α7,α9,α10 and β1-β4,as well as γ,δ,and ε,which assemble into pentamers to form different nAChR subtypes with distinct pharmacological properties in mammals.Among them α6β2*(*designates other possible subunit),α3β4 and α4β2 nAChR subtypes are potential therapeutic targets for the treatment of addiction.However,various n AChR subtypes are very difficult to pharmacologically distinguish from each other.The α6* n AChRs are expressed by dopaminergic neurons in the central nervous system,which modulate the release of dopamine and are believed to be important in mediating tobacco,morphine,cocaine and ethanol addiction.The α3β4 nAChRs present in the medial habenula with important role in influencing nicotine addiction.Blockage of α3β4 nAChRs in the medial habenula decreased the dose of nicotine that rodents would self-administer.Thus,new antagonists of α6β2* or α3β4 nA ChR subtypes are of considerable interest,which would give strategies to selectively modulate α6β2* or α3β4 nA ChR function.We characterized an α-conotoxin(α-CTx)TxIB with 16 amino acids and an α-CTx TxID with 15 amino acids from Conus textile.The sequence of TxIB is GCCSDPPCRNKHPDLCamide.The sequence of TxID is GCCSHPVCSAMSPIC with C-terminal amidation too.Both peptides with a Ⅰ-Ⅲ and Ⅱ-Ⅳ disulfide con-nectivity were chemically synthesized.The residues between Cys-Ⅱ and Cys-Ⅲ and Cys-Ⅲand Cys-Ⅳ of α-CTx are commonly referred to as loops 1 and 2,respectively.The number of residues in each of these loops is used to further classify the α-CTx.So TxIB is classified as a 4/7α-CTx,whereas the α-CTx TxIB has a 4/6 spacing.Both peptides were tested on rat nAChRs heterologously expressed in Xenopus laevis oocytes.The α-CTx TxIB blocked α6/α3β2β3 nAChR with an IC50 of 28 nmol·L^(-1),which showed little or no block

关 键 词：ACETYLCHOLINE RECEPTORS smokingcessation DRUG REHABILITATION α-conotoxins 

分 类 号：R96[医药卫生—药理学]