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1、SodiumChannelStructure,Function,GatingandInvolvementinDiseaseDavidR.Marks,M.Sc.AnOverviewSodiumChannelStructure-CurrenttheoryandTypesofNa+ChannelsSodiumChannelFunctionCurrenttheoryofinactivationModulationPharmacologyActivationAnOverviewCont’dArticle2–Na+Channel
2、GatingArticle1-Na+ChannelsandNeurodegenerativeDiseaseArticle3–Na+channelmutationandphysiologySodiumChannels-StructureComposedofα,β-1andβ-2subunits,butthelargeα-subunitscarriesmostofthefunctionalproperties4repeatedmotifs,eachwith6transmembranedomainsAlllinkedtog
3、etherContainavoltage“sensor”/ligandbindingdomain(methodofactivation)ThehydrophobicS4segment(voltage“sensor”)isfoundinallvoltagegatedNa+channelsandisabsentinligandgatedNa+channelsSelectivityfilter(shellofhydration)InactivationgateCartoonrepresentationofthe“typic
4、al”voltage-activatedsodiumchannelTypesOfNa+ChannelsVoltagegated–ChangesinmembranepolarityopenthechannelLigandgated(nicotinicacetylcholinereceptor)–Ligandbindingalterschannel/receptorconformationandopenstheporeMechanicallygated(stretchreceptor)–Physicaltorsionor
5、deformationopensthechannelporeSodiumChannels-FunctionPlayacentralroleinthetransmissionofactionpotentialsalonganerveCanbeindifferentfunctionalstates(3)-Arestingstatewhenitcanrespondtoadepolarizingvoltagechanges-Activated,whenitallowsflowofNa+ionsthroughthe-Inact
6、ivated,whensubjectedtoa“suprathreshold”potential,thechannelwillnotopenThetheoryisthattheinactivationgate“swings”shut,turningoffthechannelPleaseKeepInMindThestructureoftheNa+channelisnot100%solved,hencea“workingmodel”isdrawnbasedonbiophysical,pharmacological,phy
7、siologicalandmolecularassaysZhao(2004)writes“Themechanismofopeningandclosingisunknown,butstructuralstudiessuggest…”Na+ChannelModulationPhosphorylationsodiumchannelfunctionismodulatedbyserine/threonineandtyrosinekinasesaswellastyrosinephosphatases(Yuetal,Science
8、1997)Mutation–alteredaminoacidsequence/structurecanchangethebiophysicalpropertiesoftheNa+channelPharmacology–blockNa+channeltoreducetheconductanceProteolysis-(cleavage)Prote
