Fig.5.5A ).Tetraethylammonium (TEA+), anotherpoison,blocksK+ channels.TEA+ enterstheK+ channelfromthecytoplasmicsideandblocksthechannelbecauseTEA+ isunabletopassthroughit.Theovariesofcertainspeciesofpufferfish,alsoknownasblowfish,containTTX.RawpufferfishisahighlyprizeddelicacyinJapan.ConnoisseursofpufferfishenjoythetinglingnumbnessofthelipscausedbytheminusculequantitiesofTTXpresentintheflesh.Sushichefswhoaretrainedtoremovetheovariessafelyarelicensedbythegovernmenttopreparepufferfish.Despitetheseprecautions,severalpeopledieeachyearasaresultofeatingimproperlypreparedpufferfish.
SaxitoxinisanotherblockerofNa+ channelsthatisproducedbythereddishdinoflagellatesthatareresponsibleforso-calledredtides.Shellfisheatthedinoflagellatesandconcentratesaxitoxinintheirtissues.Apersonwhoeatstheseshellfishmayexperiencelife-threateningparalysiswithin30minutesafterthemeal.
When a nerve is depolarized very slowly, the normal threshold may be passed without the firing of an action potential; this phenomenon is called accommodation. Both Na+ and K+ channels are involved in accommodation. In response to membrane depolarization, gNa first increases and then, a short time later, decreases. This is due to the opening of the activation gates and closing of the inactivation gates of the Na+ channels. Normally, membrane depolarization to threshold or beyond triggers an action potential; however, the explosive depolarization of the action potential can occur only if a critical number of Na+ channels are recruited. Thus if a cell is slowly depolarized, Na+ channels can become inactivated even without the occurrence of an action potential, and the pool of available noninactivated Na+ channels (i.e., channels in the closed state) can be reduced to the point at which a stimulus to may not be able to recruit a sufficient number of Na+ channels to generate an action potential. An additional factor in causing accommodation is that K+ channels open slowly in response to the depolarization. The increased gK tends to oppose depolarization of the membrane, which makes it even less likely to fire an action potential.
When a cell is refractory, it is either completely unable to fire an action potential or it requires a much stronger stimulation than usual. During much of the action potential, the cell is completely refractory because it will not fire another action potential no matter how strongly it is stimulated. This absolute refractory period (see
Fig. 5.4 ) occurs when a large fraction of the Na+ channels are inactivated and therefore cannot be reopened until the membrane is repolarized. During this period, the critical number of Na+ channels required to produce an action potential cannot be recruited.
Inaninheriteddisordercalledprimary hyperkalemic paralysis, patientshaveepisodesofpainfulspontaneousmusclecontractionsfollowedbyperiodsofparalysisoftheaffectedmuscles.Thesesymptomsareaccompaniedbyelevated[K+]inplasmaandextracellularfluid.Somepatientswiththisdisorderhavemutationsofvoltage-gatedNa+ channelsthatresultinadecreasedrateofvoltageinactivation.Thisresultsinlonger-lastingactionpotentialsinskeletalmusclecellsandincreasedeffluxofK+ duringeachactionpotential,whichcanraiseextracellular[K+].