chlorideionchannels

Zhuang-LiHuDept.PharmacologyIn1990，firstmemberofClCChlorideChannelFamilyclonedsuccessfullybyJentsch。Distributedwidelyinallorganismalplasmamembranesandintracellularorganellemembranes。Calledanionchannels,predominantlypermeabletoCl-，thentoI-，Br-，F-，NO3-，PO43-,etc.IntroductionClassification◙Voltage-gatedCl-channel:ClCchloridechannelfamily◙cAMPactivatedCl-channel:CysticFibrosisTransmembraneconductanceRegulator(CFTR)◙Swelling-activatedCl-channel◙Calcium-activatedCl-channel◙Ligand-gatedCl-channel:GABAandGlycinereceptorsAccordingtoopenningmechanismskeletalmusclesBrainHeartKidneyDistributionHEARTSixchloridecurrentsICl.PKA(AC-cAMP–PKA)ICl.PKC(PKC)ICl.ATP(purinereceptor)ICl.swell(cellularswelling)ICl.h(background)ICl.Ca(calcium-activated)CFTRClC-3CaCCClC-2ICl.irFourgenesheartfailure,arrhythmia,myocardialischemia1.ICl.PKACodedbyCFTRgeneRegulatedbyAC-cAMP-PKApathwayDistributedmainlyincardiacventricleofguineapig,rabbitandcat.Human?2.ICl.PKCCodedbyCFTRgene?PKCincardiacCFTRmayberegulatedbypurinsignalingpathwayand/orAngreceptors.3.ICl.ATPOriginfrompurinereceptoractivatingofCFTRRegulatedbydoublesignalingpathway:PKAandPKCphosphorylation4.ICl.swellActivatedbyincreasingcellvolume,deactivatedinisosmoticsolutionDensity:atriummuscle＞ventricularmuscleIschemia-reperfusion→cellswelling→activatingICl.vol→arrhythmia5.ICl.CaIto1sensitiveto4-AP,insensitivetoCa2+.Ito2minorsensitivetoCa2+,insensitiveto4-APICl.Ca。Ito6.OtherClCchloridechannelsmammalianheart:ClC-2、3、4、5、6、7KIDNEY•ClCchloridechannel•CFTRchloridechannel•Swelling-activatedCl-channel•Calcium-activatedCl-channel1.ClCchloridechannel:allexceptforClC-1ClC-K1&ClC-K2→ClC-K:specialspicesinkidney.medullaryloopClC-2:maybeinproximaltubuleClC-3:BtypeintercalarycellincollectingductClC-5:proximaltubule、ascendingthicklimbofHenle'sloopandcollectingductClC-4、ClC-6&ClC-7:proximaltubule2.CFTRdistalconvolutedtubule,corticalcollectingduct,internalmedullarycollectingduct3.CaCCwidelydistributedinkidney.distalconvolutedtubule,proximalconvolutedtubuleandcollectingduct4.Swelling-activatedCl-channel(regulatoryvolumedecrease,RVD）corticalcollectingduct、internalmedullarycollectingductandnephrictubuleElectronexcitabilityregulationFunctionsSkeletalmuscleClC-1:stabilizerestingmembranepotential(congenitalmyotonia)；Smoothmusclecell:regulatevasoconstrictionandmechanicaltensionreaction(CaCCandVRAC)；Neuron:reacttoGABA。细胞兴奋性调节，跨上皮物质转运，细胞容积调节和细胞器酸化作用，细胞免疫应答，细胞增殖、分化、凋亡TransportersandchannelswhichdeterminethedistributionofCl–inamammaliancell.TransepithelialtransportChloridechannelsasmajorplayersintransepithelialtransport.Cellvolumecontrolextracellularhypotonic→potassiumchannelsandchloridechannelopenning→internalsaltefflux→↓osmoticpressureIonicbalanceregulationmaintainelectricityneutralityFunctionsClCchloridechannelfamilyFirstidentifiedin1990,namedClC-0。9codinggenes，dividedinto3groups。ClC家族氯通道的分组，分布和在人染色体上的位置细胞膜细胞器膜也存在于细胞膜molecularstructure13lyophobicfunctionaldomain（D1-D13）.2seriesCBSfunctionaldomainincarboxylterminus.D4domain,D13domain,CBS2Cystanthionineβsynthetasecrystalstructure：homodimer18α-spiralA-IantiparallelJ-Rdouble-barreled（双筒枪）structure慢闸门快闸门Slowgate:commonshared“10秒”控制两个孔道Fastgate:respective“10毫秒”控制各自孔道ClC-1：Onlyinskeletalmuscle，dependingonSMelectricitygeneticmutationleadtomyotoniacandidategeneforcongenitalmyotoniaClC-2：RegulatecellvolumeRegulateneuronalCl-concentration,influenceGABAsynaptictransmissionTargetforcysticfibrosistherapyKidneyandlungdevelopment,gastricacidsecretionfunctionClC-Ka、ClC-Kb：Urinaryconcentration（ClC-K1）。nephrictubuletransepithelialtransportandCl-recirculating（ClC-Kb）。Batter’sSyndromⅢ、ⅣClC-3：Incellularorganmembranes。Candidateproteinforswelling-activatedCl-channel？（ClC-3B）ClC-4：gutCl-secretionClC-5：pinocytosis,DentdiseaseClC-6、CLC-7：nonfunctionalexpressionfunction◙ClCandcellvolumeregulationosmoticpressurechang→cellvolumechangeClC-3:ICl.volcellvolumeregulationVSOACsRVDfunctionClC◙ClCandcellmigrationClC-2、ClC-3:NeurogliomamigrationandinvasionCriticalroleinG1/Spoint:toSphaseorbacktoG0phasefunction•Voltage-dependence•Permeability：Cl-＞Br-＞I-•RegulatedbyextracellularanionandpHelectrophysiologicalcharacteristicsCLC家族氯通道的电生理特性ClC-0ClC-1ClC-2ClC-40mV开放，超级化失活内向整流性，超级化失活超级化激活去极化激活，外向整流性Voltage-dependentgatingoftheClC-0Cl-channel.药理学特性CFTRTransepithelialsalttransport,moistureflow,ionconcentrationregulation,electrolyteandliquidsecretion.ABC(ATP-bindingcassette)transporterfamily，voltage-independent.MSD1MSD2molecularstructure12transmembranesegment2membrane-spanningdomain（MSD1、MSD2）nucleotidebindingdomain（NBD1、NBD2）MSD1-NBD1-R(regulatorydomain)-MSD2-NBD2membraneproteinR-domain:multiplePKAandPKCphosphorylationsites→CFTRopenNBD1:determinechannelopenandclosetime;NBD2:regulatechannelopentime。functionRegulateprotein•InhibitionofENaC,thendown-regulationofNa+reabsorption.•EnhancementofROMK2potassiumchannelsensitizationtoglibenclamide.•Down-regulationofCaCC.•InhibitionofVRAC.BiologicalcharacteristicsATP在NBD1水解的速率决定通道关闭的时间；ATP在NBD2水解速率决定通道开放时间。ATP与NBD2结合ATP水解ATP与NBD1结合ATP水解