Quantitative Modeling of Currents from a Voltage Gated Ion Channel Undergoing Fast Inactivation 英文参考文献.docVIP

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Quantitative Modeling of Currents from a Voltage Gated Ion Channel Undergoing Fast Inactivation 英文参考文献.doc

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QuantitativeModelingofCurrentsfromaVoltageGated IonChannelUndergoingFastInactivation CarlosJ.Camacho* DepartmentofComputationalBiology,UniversityofPittsburgh,Pittsburgh,Pennsylvania,UnitedStatesofAmerica Abstract Ionchannelsplayacentralroleinsettinggradientsofionconcentrationandelectrostaticpotentials,whichinturnregulate sensory systems and other functions. Based on the structure of the open configuration of the Kv1.2 channel and the suggestionthatthetwoendsoftheN-terminalinactivatingpeptideformabivalentcomplexthatsimultaneouslyblocksthe channel pore and binds to the cytoplasmic T1 domain, we propose a six state kinetic model that for the first time reproduces the kinetics of recovery of the Drosophila Shaker over the full range of time scales and hyperpolarization potentials, including tail currents. The model is motivated by a normal mode analysis of the inactivated channel that suggeststhatadisplacementconsistentwithmodelsoftheclosedstatepropagatestotheT1domainviatheS1-T1linker. This motion stretches the bound (inactivating) peptide, hastening the unblocking of the pore. This pulling force is incorporatedintotheratesoftheopentoblockedstates,capturingthefastrecoveryphaseofthecurrentforrepolarization events shorter than 1ms. If the membrane potential is hyperpolarized, essential dynamics further suggests that the T1 domainreturnstoaconfigurationwherethepeptideisunstretchedandtheS1-T1linkerisextended.Couplingthisnovel hyperpolarizedsubstatetotheclosed,openandblockedporestatesisenoughtoquantitativelyestimatethenumberof open channels as a function of time and membrane potential. A straightforward prediction of the model is that a slow rampingofthepotentialleadstoverysmallcurrents. Citation: Camacho CJ (2008) Quantitative Modeling of Currents from a Voltage Gated Ion Channel Undergoing Fast Inactivation. PLoS ONE 3(10): e3342. doi:10.1371/journal.pone.0003342 Editor:MarcHerant,BostonUniversity,UnitedStatesofAmerica ReceivedJune12,2008;AcceptedSeptember11,2008;Publish