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