The end of the rising phase and the subsequent falling (repolarization) phase of the action potential is the result of two processes: a reduction in gNa and an increase in gK. The rise in gK is simply a consequence of membrane depolarization, which increases the probability that the K+ channel will be open. The decrease in gNa results from two •Fig. 5.7 The Action Potential and the Conductance and Currents That Underlie the Action Potential With Regard to Time. NotethattheincreasedconductanceforNa+ (gNa),aswellasitsinwardflow,isassociatedwiththerisingphaseoftheactionpotential,whereastheslowerincreaseinconductanceforK+ (gK),aswellasitsoutwardflow,isassociatedwithrepolarizationofthemembraneandwithafterhyperpolarization.ThereductionintheNa+ current(INa)beforethepeakoftheactionpotential(eventhoughgNaisstillhigh)isduetoinactivationoftheNa+ channels.(RedrawnfromSquiresLR,etal:Fundamental Neuroscience. 2nded.SanDiego,CA:AcademicPress;2002.) factors. First, Na+ channels are inactivated as a result of the closing of the inactivation gate with depolarization. Unlike the activation gate, which can flip between states even when the membrane is depolarized, the inactivation gate, once closed, remains closed until significant repolarization occurs. Second, as the gK/gNa ratio increases (as a result of both inactivation of Na+ channels and opening of K+ channels), the membrane begins to repolarize, and this repolarization acts to shut the activation gate of the Na+ channel. The closure of both voltage-gated Na+ and K+ channels during the falling phase brings the membrane back to its resting state. If only Na+ channels had opened during the action potential (as is the case for some axons), the membrane would simply return to its rest potential. If voltage-gated K+ channels also had opened during the action potential, an afterhyperpolarization would be present because these K+ channels close slowly in response to hyperpolarization.
Knowledgeofthemolecularstructureofchannelshasincreasedtheunderstandingofthebasisoftheirproperties.Forexample,mostchannelsarehighlyselectiveforaparticularion.First,ifthechannelwallsarelinedwitheitherpositiveornegativecharges,theneithercationsoranionscanbeexcluded;however,mostchannelsarealsodifferentiallypermeablebydifferentionsofthesamecharge.Thisfurtherselectivityappearstobetheresultofrequiringionstobecomedehydratedastheypassthroughthenarrowestpartofachannel,knownastheselectivity filter. Ionsinsolutionarehydrated(aresurroundedbyashellofH2Omolecules),andtheradiusofthishydrationshellisdifferentforeachtypeofion.InNa+ andK+ channels,tomakedehydrationenergeticallypossible,theporeofthechannelislinedwithnegativelypolarizedaminoacidsubstituentsofaparticulargeometry,andthesesubstituentssubstituteforthewatermolecules.Suchsubstitution,however,requiresclosematchingofthefilter’ssizetotheion’shydrationshell.Becauseeachionhasadifferent-sizedshell,aparticularchannelwillbestallowpassageofoneparticularionicspecies.
Tetrodotoxin (TTX), oneofthemostpotentpoisonsknown,specificallyblockstheNa+ channel.TTXbindstotheextracellularsideofthesodiumchannel(see