Another poison, tetraethylammonium (TEA+), blocks K+ channels by entering the channel from the cytoplasmic side. TEA+ is unable to pass through the channel, leading to its blockage. Certain species of pufferfish, also known as blowfish, contain tetrodotoxin (TTX) in their ovaries. Raw pufferfish is a delicacy in Japan, and those who consume it enjoy the tingling numbness of the lips caused by the small amounts of TTX present in the flesh. Sushi chefs trained to safely remove the ovaries are licensed by the government to prepare pufferfish. However, despite these precautions, several people die each year from eating improperly prepared pufferfish.

Saxitoxin, produced by reddish dinoflagellates responsible for red tides, is another blocker of Na+ channels. Shellfish consume the dinoflagellates and concentrate saxitoxin in their tissues. Individuals who consume these shellfish may experience life-threatening paralysis within 30 minutes after the meal.

The phenomenon of accommodation occurs when a nerve is depolarized very slowly and the normal threshold is passed without firing an action potential. Both Na+ and K+ channels are involved in accommodation. In response to membrane depolarization, gNa initially increases and then decreases after a short time. This is due to the opening of the activation gates and closing of the inactivation gates of the Na+ channels. Normally, membrane depolarization triggers an action potential, but the explosive depolarization can only occur if a critical number of Na+ channels are recruited. Therefore, if a cell is slowly depolarized, Na+ channels can become inactivated without the occurrence of an action potential. This can reduce the pool of available noninactivated Na+ channels to a point where a stimulus may not be able to recruit enough Na+ channels to generate an action potential. Additionally, K+ channels open slowly in response to depolarization, further opposing membrane depolarization and reducing the likelihood of firing an action potential.

During refractory periods, a cell is either completely unable to fire an action potential or requires a much stronger stimulation than usual. The absolute refractory period occurs when a large fraction of Na+ channels are inactivated and 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.

In primary hyperkalemic paralysis, an inherited disorder, patients experience episodes of painful spontaneous muscle contractions followed by periods of paralysis in the affected muscles. These symptoms are accompanied by elevated levels of K+ in plasma and extracellular fluid. Some patients with this disorder have mutations in voltage-gated Na+ channels, resulting in a decreased rate of voltage inactivation. This leads to longer-lasting action potentials in skeletal muscle cells and increased efflux of K+ during each action potential, which can raise extracellular K+ levels.
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+].