Ca2+ channelsCheng Long, chenglong_scnu@qq.comSchool of Life Sciences, South China Normal UniversityMar 06, 20121933华南轩花大学UNIVERSITYSOUTHCHINNORMN
Cheng Long, chenglong_scnu@qq.com School of Life Sciences, South China Normal University Mar 06, 2012 Ca2+ channels
The outline...Required Readings:CatterallWA(2ooo)Structureandregulationofvoltage-gatedCa2+channels.Annu.Rev.CellDev.Biol.16:521-555.LacinovaL.(2o05)Voltage-dependent calciumchannels.GenPhysiolBiophysSuppl1:1-78.Taylor CW, Prole DL,Rahman T.(2oo9)Ca2+ channels on the move.Biochemistry48(51):12062-12080MinorDLJr,FindeisenF.(2010)Progressinthestructuralunderstandingofvoltage-gatedcalciumchannel(CaV)functionandmodulation.Channels(Austin).4(6):459-474Further Readings:CatterallWA,FewAP.(2oo8)Calciumchannel regulationandpresynapticplasticity.Neuron.59(6):882-901.XuJ,HeL,WuLG.(2oo7)RoleofCa2+channelsinshort-termsynapticplasticityCurrOpinNeurobiol.17(3):352-359EvansRM,ZamponiGW.(2oo6)PresynapticCa2+channels--integrationcentersforneuronalsignalingpathways.TrendsNeurosci.29(11):617-624
The outline. Required Readings: Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16: 521–555. Lacinová L. (2005) Voltage-dependent calcium channels. Gen Physiol Biophys. Suppl 1: 1-78. Taylor CW, Prole DL, Rahman T. (2009) Ca2+ channels on the move. Biochemistry. 48(51): 12062-12080. Minor DL Jr, Findeisen F. (2010) Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin). 4(6): 459-474. Further Readings: Catterall WA, Few AP. (2008) Calcium channel regulation and presynaptic plasticity. Neuron. 59(6): 882-901. Xu J, He L, Wu LG. (2007) Role of Ca2+ channels in short-term synaptic plasticity. Curr Opin Neurobiol. 17(3): 352-359. Evans RM, Zamponi GW. (2006) Presynaptic Ca2+ channels-integration centers for neuronal signaling pathways. Trends Neurosci. 29(11): 617-624
The outline...This class will cover:Ca2+currenttypesStructureofCa2+channelsMolecular properties of Ca2+ channelsRegulationofCa2+channelsWhole-cell recording of Ca2+ channel currents
The outline. This class will cover: Ca2+ current types Structure of Ca2+ channels Molecular properties of Ca2+ channels Regulation of Ca2+ channels Whole-cell recording of Ca2+ channel currents
CellularDependenceon Ca2+signalingStimulus ResponsePhysiologicalIntracellular StoresActivationCa?+ channelsCALCIUMSINALING PATHWAYContractionCa2+ SecretionERVSMetabolismGPCRADCYFLNEAMCon ot C2-Kinase signalingCell DeatheManytanetmSmall moleculeApoperirCeostioProliferationsignalingCAMEHeansaroLoogtomteymonPLCSOevthfSecretionStore operatedFLCPADOFLOFOELROnebne2trefillingACpeonDAOLearningPaerthinyteaIPXAmADPFRCHADP& MemoryMADHxocyo28EFertilizationD4020 9/26/05More Signaling!KEGGCa2+ signalingpathway
Cellular Dependence on Ca2+ signaling Ca2+ Secretion Kinase signaling Store operated refilling Ca2+ channels Intracellular Stores Small molecule signaling KEGG Ca2+ signaling pathway Physiological Activation Contraction Metabolism Cell Death Proliferation Secretion Learning & Memory Fertilization More Signaling! Stimulus Response
Table1.PhenotypicFeaturesof TimothySyndromePhenotypeAffected* (%)TimothysyndromecausedHeartQTprolongation100Arrhythmiaby mutation in a Ca2+71(1)Ventriculartachyarrhythmia94(2)Bradycardia,AVblock59Patent ductus arteriosus29Patentforamenovalechannel gene18Ventricularseptaldefects6Tetralogy ofFallot35CardiomegalyCNS60Autism80Autismspectrumdisorders25Mental retardation21SeizureseUmbilicalcord13TwovesselGastrointestinal31GagreflexSkin100Syndactyly100Bald atbirthFace53DysmorphiaEyes25MyopiaNose29SinusitisTeeth100SmallCavities50Lungs47Pneumonia/bronchitis21Pulmonaryhypertension8Hypothyroidism33Hypocalcemia36Hypoglycemia33HypothermiaMuscoskeletal40Hypotonia43Immunodeficiency/recurrentinfections*Nine affected individuals were male, and eight were female"Atrioventricularblock,Splawskietal..Cell2004
Timothy syndrome caused by mutation in a Ca2+ channel gene Splawski et al., Cell 2004
Timothy syndrome caused by de novo mutation in aCay1.2 splice variantBModeled action李808#8#)eo50mspotentials are longerueoeyRequires35%reduction in mutantchannelcurrentto getback to wtWTCay1.2G406RCay1.2MutantCa2+channelsstay openlongerSmall changeinmodeledAOSAO0inactivation of200ms200msheterozygousSplawski et al.,Cell 2004channels
Timothy syndrome caused by de novo mutation in a CaV1.2 splice variant Modeled action potentials are longer Requires 35% reduction in mutant channel current to get back to wt Mutant Ca2+ channels stay open longer Small change in modeled inactivation of heterozygous Splawski et al., Cell 2004 channels
IntroductionCa2+channelsinmanydifferentcell typesactivateuponmembrane depolarization and mediate Ca2+ influx inresponsetoactionpotentialsandsub-thresholddepolarizingsignals.Ca2+enteringthecell throughvoltage-gatedCa2+channelsserves as the second messengerof electrical signalinginitiating intracellular events suchas contraction,secretion,synaptictransmission,andgeneexpression.Multipletypes of Ca2+ currents havebeen identified bytheirphysiologicalandpharmacologicalpropertiesandhavebeen correlatedwithclonedCa2+ channel subunitscharacterizedbyexpressioninvitro
Introduction Ca2+ channels in many different cell types activate upon membrane depolarization and mediate Ca2+ influx in response to action potentials and sub-threshold depolarizing signals. Ca2+ entering the cell through voltage-gated Ca2+ channels serves as the second messenger of electrical signaling, initiating intracellular events such as contraction, secretion, synaptic transmission, and gene expression. Multiple types of Ca2+ currents have been identified by their physiological and pharmacological properties and have been correlated with cloned Ca2+ channel subunits characterized by expression in vitro
NucleusCRECRECA1CREB-1CPAMAPkinaseCAMPkinaseR(AB)CA3CA1CAMPNMDAAdenylylCareceptor1cyclaseSoO1CaAMPAcalmodulinereceptor福Enhanced9PtransmitterGluCalTyrosinecalmodulinPKcreleasekinase (Fyn)?+kinaseEffectorsRegulators(tPA,BDNF)(C/EBPbeta)Retrogradesignal generatorNewAMPANO?receptorEarlyLTPRetrogrademessengerNMDAereceptorGlu?AMPAreceptorLate LTP(newsynapses)
Calciummodelof plasticityinductionAMPARsCa2+Group INMDARSmGluRs大MCPGOtherG-protein2+CacoupledreceptorsINTRACELLULARSTORESVGCCPLASTICITYCASCADESlidefromMikeFriedlandel
Slide from Mike Friedlander NMDARs Group I mGluRs PLASTICITY CASCADE INTRACELLULAR STORES Ca2+ Ca2+ VGCC AMPARs IP3 Other G-protein coupled receptors XAPV X MCPG
Cells must interpret Ca2+ signalsCa2+signalsvaryin.Time.LocationAmplitudeCourtesy of Natalia Shirokova,PhD
Cells must interpret Ca2+ signals Ca2+ signals vary in Time Location Amplitude Courtesy of Natalia Shirokova, PhD