The action potential undergoes two processes to transition from the rising phase to the falling phase: a decrease in gNa and an increase in gK. The increase in gK occurs as a result of membrane depolarization, which enhances the likelihood of the K+ channel being open. On the other hand, the decrease in gNa is influenced by two factors. Firstly, depolarization leads to the inactivation of Na+ channels as the inactivation gate closes. Unlike the activation gate, which can switch between states even during membrane depolarization, the inactivation gate remains closed until significant repolarization occurs. Secondly, as the gK/gNa ratio increases due to the inactivation of Na+ channels and the opening of K+ channels, the membrane starts repolarizing, causing the activation gate of the Na+ channel to close. The closure of both voltage-gated Na+ and K+ channels during the falling phase returns the membrane to its resting state. In cases where only Na+ channels open during the action potential, the membrane would simply return to its resting potential. However, if voltage-gated K+ channels also open during the action potential, an afterhyperpolarization occurs as these K+ channels close slowly in response to hyperpolarization.

Understanding the molecular structure of channels has improved our understanding of their properties. Channels typically exhibit high selectivity for specific ions. If the channel walls are lined with positive or negative charges, neither cations nor anions can be excluded. However, most channels also show differential permeability for ions of the same charge. This selective permeability is thought to be a result of ions becoming dehydrated as they pass through the narrowest part of the channel, known as the selectivity filter. Ions in solution are surrounded by a hydration shell of water molecules, and the radius of this hydration shell varies for different types of ions. In Na+ and K+ channels, the pore of the channel is lined with negatively polarized amino acid substituents of a specific geometry, allowing for the energetic possibility of dehydration. These substituents replace the water molecules. However, this substitution requires precise matching of the filter's size to the ion's hydration shell, as each ion has a different-sized shell. This specific channel design allows for the passage of a particular ionic species.

Tetrodotoxin (TTX), one of the most potent poisons known, selectively blocks the Na+ channel. TTX binds to the extracellular side of the sodium channel.
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