Na+ channelsCheng Long, chenglong_scnu@qq.comSchool of Life Sciences, South China Normal UniversityMar. 13, 20121933华南轩花大学UNIVERSITYSOUTHCHINNORMN
Cheng Long, chenglong_scnu@qq.com School of Life Sciences, South China Normal University Mar. 13, 2012 Na + channels
What'syourassociationwithNat channels?Atargetforspecific,clinicallyimportant,localanaestheticeffectsinneuronsWidespreaduse oflocal anaestheticsforwelloveracentury
What’s your association with Na+ channels? A target for specific, clinically important, local anaesthetic effects in neurons Widespread use of local anaesthetics for well over a century
The outline...RequiredReadings:Marban E,YamagishiT,Tomaselli GF.(1998) Structureandfunctionofvoltage-gatedsodiumchannels.JPhysiol.508(3):647-57GoldinAl.(2o03)Mechanismsofsodiumchannelinactivation.CurrentOpinioninNeurobiology2003,13(3):284-290ScheuerT(2011)Regulationofsodiumchannel activitybyphosphorylation.Seminars in Cell &Developmental Biology22(2):160-165.http://www.sciencedirect.com/science/article/pil/S1084952110001643RuanY,LiuN,PrioriSG.(2oo9)Sodiumchannelmutationsandarrhythmias.Nat Rev Cardiol.6:337-348.FurtherReadings:Dib-HajSD,CumminsTR,BlackJA,WaxmanSG.(2010)Sodiumchannels innormal and pathological pain.Annu RevNeurosci33:325-247Dib-HajSD,BinshtokAM,CumminsTR,JarvisMF,SamadT,Zimmermann K.(2009)Voltage-gated sodium channels in painstates:rolein pathophysiology and targetsfortreatmentBrainResRev.60:65-83
The outline. Required Readings: Marban E, Yamagishi T, Tomaselli GF. (1998) Structure and function of voltage-gated sodium channels. J Physiol. 508(3): 647-57. Goldin Al. (2003) Mechanisms of sodium channel inactivation. Current Opinion in Neurobiology 2003, 13(3): 284–290. Scheuer T (2011) Regulation of sodium channel activity by phosphorylation. Seminars in Cell & Developmental Biology. 22(2): 160-165. http://www.sciencedirect.com/science/article/pii/S1084952110001643 Ruan Y, Liu N, Priori SG. (2009) Sodium channel mutations and arrhythmias. Nat Rev Cardiol. 6: 337-348. Further Readings: Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. (2010) Sodium channels in normal and pathological pain. Annu Rev Neurosci. 33: 325-247. Dib-Hajj SD, Binshtok AM, Cummins TR, Jarvis MF, Samad T, Zimmermann K. (2009) Voltage-gated sodium channels in pain states: role in pathophysiology and targets for treatment. Brain Res Rev. 60: 65-83
The outline...Thisclasswill cover:TypesandstructureofNatchannelsBiochemical,molecularand genetic propertiesPhysiological rolesand regulationPharmacological significance and disorders
The outline. This class will cover: Types and structure of Na + channels Biochemical, molecular and genetic properties Physiological roles and regulation Pharmacological significance and disorders
IntroductionSodium channelsare responsibleforactionpotentialinitiation andpropagation in excitable cells, including nerve, muscle,andneuroendocrinecelltypesThey are also expressed at low levels in nonexcitable cells, wheretheirphysiological roleisunclear.Sodiumchannelsarethefoundingmembers oftheionchannelsuperfamilyintermsoftheirdiscoveryasaproteinanddeterminationoftheiraminoacidsequence
Introduction Sodium channels are responsible for action potential initiation and propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types. They are also expressed at low levels in nonexcitable cells, where their physiological role is unclear. Sodium channels are the founding members of the ion channel superfamily in terms of their discovery as a protein and determination of their amino acid sequence
IntroductionSodium channels mediate fast depolarization and conductelectrical impulses throughout nerve, muscle and heart.Sodiumchannels haveamodulararchitecture,with distinctregions for the pore and the gates.Theseparationisfarfromabsolute,however,withextensiveinteraction among thevariouspartsofthechannel.Sodium channels are not static:they moveextensively in thecourse of gating and ion translocation (at a molecularlevel)SodiumchannelsbindIocalanaestheticsandvarioustoxins.Insomecases,therelevantsiteshavebeenpartiallyidentifiedSodium channels are subject to regulation at the levels oftranscription,subunit interaction and post-translationalmodification (notablyglycosylationand phosphorylation)
Introduction Sodium channels mediate fast depolarization and conduct electrical impulses throughout nerve, muscle and heart. Sodium channels have a modular architecture, with distinct regions for the pore and the gates. The separation is far from absolute, however, with extensive interaction among the various parts of the channel. Sodium channels are not static: they move extensively in the course of gating and ion translocation (at a molecular level). Sodium channels bind local anaesthetics and various toxins. In some cases, the relevant sites have been partially identified. Sodium channels are subject to regulation at the levels of transcription, subunit interaction and post-translational modification (notably glycosylation and phosphorylation)
IntroductionSodium channels transmit depolarizing impulses rapidlythroughout cells and cell networks,thereby enabling co-ordination of higherprocesses ranging from locomotiontocognition.Natchannelsarerichlyconcentrated inaxonsand inmuscle.wherethey areoftenthemostplentiful ionchannels.Mammalianheartcells,forexample,typicallyexpressmorethan 100 000 Nat channels, but only 20 000 or so L-type Ca2+channels and fewer copies of eachfamily of voltagedependentKtchannelsNatchannels consist of various subunits,but only theprincipal (α)subunitisrequired
Introduction Sodium channels transmit depolarizing impulses rapidly throughout cells and cell networks, thereby enabling coordination of higher processes ranging from locomotion to cognition. Na+ channels are richly concentrated in axons and in muscle, where they are often the most plentiful ion channels. Mammalian heart cells, for example, typically express more than 100 000 Na+ channels, but only 20 000 or so L-type Ca2+ channels and fewer copies of each family of voltagedependent K+ channels. Na+ channels consist of various subunits, but only the principal () subunit is required
HistorySodiumchannelsareof special importanceforthehistory ofphysiologyElucidation oftheirfundamental properties inthesquid axonlaunched modernchanneltheory.Inparticular,theworkofHodgkinandHuxleyonsodiumchannelsrevolutionizedelectrophysiologyby elegantlydissectingthe elementaryprocesses ofgatingandpermeation.Sodium channelsfirstappearphylogeneticallyinthejellyfishwheretheyenabletheorganismtotransmitelectricalsignalsefficientlythroughouta dispersed neural net.Sodium channels werethe first voltage-dependent ion channelsto becloned,usheringinthe eraof heterologousexpression andmolecular manipulation.The cloning happily coincided with thedevelopmentofpatch-clamptechniques,whichenabledsinglechannelrecordings
History Sodium channels are of special importance for the history of physiology. Elucidation of their fundamental properties in the squid axon launched modern channel theory. In particular, the work of Hodgkin and Huxley on sodium channels revolutionized electrophysiology by elegantly dissecting the elementary processes of gating and permeation. Sodium channels first appear phylogenetically in the jellyfish, where they enable the organism to transmit electrical signals efficiently throughout a dispersed neural net. Sodium channels were the first voltage-dependent ion channels to be cloned, ushering in the era of heterologous expression and molecular manipulation. The cloning happily coincided with the development of patch-clamp techniques, which enabled singlechannel recordings
Classification of Nat channelsSubunitsNav1.1Nav1.2Voltage-gatedNav1.3Nav1.4Nav1.5Non-voltage-gatedNav1.6Nav1.7ExchangersNav1.8Nav1.9
Classification of Na + channels Voltage-gated Non-voltage-gated Exchangers Subunits Nav1.1 Nav1.2 Nav1.3 Nav1.4 Nav1.5 Nav1.6 Nav1.7 Nav1.8 Nav1.9
NomenclatureofNatchannelsThefunctional propertiesof theknownsodiumchannels arerelativelysimilar.It utilizesa numerical systemtodefine subfamilies and subtypesbased onsimilaritiesbetweentheamino acid sequencesofthechannels.Inthisnomenclature system,the name ofan individual channelconsistsofthechemicalsymbolof theprincipal permeatingion(Na)withtheprincipalphysiologicalregulator(voltage)indicatedas a subscript (Nay).The number following the subscriptindicatesthe gene subfamily(currently onlyNay1),andthenumberfollowingthe full pointidentifiesthe specific channelisoform (e.g-,Nay1.1).This last numberhasbeen assignedaccording to the approximate order in which each genewasidentified.Splice variantsof eachfamily memberareidentifiedbylowercaselettersfollowingthe number (e.g-,Nay1.1a)Alloftheninesodiumchannelisoforms may be consideredmembersofonefamily
Nomenclature of Na + channels The functional properties of the known sodium channels are relatively similar. It utilizes a numerical system to define subfamilies and subtypes based on similarities between the amino acid sequences of the channels. In this nomenclature system, the name of an individual channel consists of the chemical symbol of the principal permeating ion (Na) with the principal physiological regulator (voltage) indicated as a subscript (Na V). The number following the subscript indicates the gene subfamily (currently only Na V1), and the number following the full point identifies the specific channel isoform (e.g., Na V1.1). This last number has been assigned according to the approximate order in which each gene was identified. Splice variants of each family member are identified by lowercase letters following the number (e.g., Na V1.1a). All of the nine sodium channel isoforms may be considered members of one family