CHAPTER 5 Generation and Conduction of Action Potentials •Fig. 5.6 A, A single channel is electrically isolated using a micropipette applied to the cell membrane. An amplifier records the current passing through the channel. B, Each line represents the current passed through a K+ channel as it spontaneously opens. The transmembrane voltage progressively depolarizes from top to bottom, increasing both the probability of channel opening and the amplitude of the current. C, A graph shows the probability of channel opening versus membrane depolarization. D, A graph depicts the transmembrane voltage (lower tracing, right-sided scale) and the current density from a population of Na+ channels (upper tracing, left-sided scale) isolated in a similar patch to that in A (except it contains several Na+ channels). At resting potential, there is no current flow. With depolarization to 0mV, there is an inward Na+ current that is curtailed even as the depolarization continues due to the closing of the channels' inactivation gates. After a brief return to resting potential, another depolarization to 0mV evokes inward current flow, but it is smaller and briefer because there has not been enough time for most of the slow inactivation gates to open. (B, C, and D are redrawn from http://www.physiologymodels.info/electrophysiology).
Na+ channels have a voltage-sensitive gate (activation gate) that opens with depolarization, increasing the probability of being open. Unlike K+ channels, Na+ channels open only at the onset of depolarization and then remain closed. This suggests that Na+ channels have a second gate (inactivation gate) that closes as the membrane is depolarized. Therefore, any Na+ current conducted by these channels will be transient because depolarization increases the probabilities of both the activation gate opening and the inactivation gate closing. The Na+ channel has two closed states: one with the activation gate closed, referred to as "closed," and one with the inactivation gate closed, referred to as "inactivated." The channel is called "inactivated" when the second gate closes because it remains closed until the membrane is repolarized. In contrast, the activation gate can open and close at all membrane potentials with varying probabilities.
Understanding the gating behavior of Na+ and K+ channels helps explain how the action potential is generated through their interaction (assuming that both gNa and gK change during the action potential). The action potential starts with a rapid increase in Na+ conductance (gNa; Fig. 5.7). This increase reflects the opening of many Na+ channels in response to depolarization. The open channels allow the influx of Na+ ions, further depolarizing the membrane. This positive feedback loop accounts for the explosive nature of the action potential: the Na+ current depolarizes the membrane, leading to more Na+ channels opening, which in turn increases the Na+ current. In summary, the voltage-dependent opening of Na+ channels and the depolarizing action of the Na+ current contribute to the rising phase of the action potential.
CHAPTER 5 Generation and Conduction of Action Potentials •Fig. 5.6 A, Amicropipetteisappliedtothecellmembraneandsufficientsuctionisappliedtoelectricallyisolateasinglechannelatthetip.Anamplifierrecordsthecurrentthatpassesthroughthechannel.B, EachlineshowsthecurrentpassedthroughaK+ channelasitopensspontaneously.Notethatasthetransmembranevoltageisprogressivelydepolarized(fromtoptobottom),boththeprobabilitythatthechannelwillopenandtheamplitudeofthecurrentareincreased.C, Agraphoftheprobabilitythatthechannelwillopenversusmembranedepolarization.D, Agraphoftransmembranevoltage(lowertracing,right-sidedscale)andthecurrentdensityfromapopulationofNa+ channels(uppertracing,left-sidedscale)isolatedinapatchsimilartothatinA (exceptthatitcontainsseveralNa+ channels).Initially,atrestingpotential,thereisnocurrentflow.Withdepolarizationto0mV,thereisaninwardNa+ currentthatiscurtailedevenwhilethedepolarizationcontinues.Thisisduetotheclosingofthechannels’inactivationgates.Afterabriefreturntorestingpotential,anotherdepolarizationto0mVevokesinwardcurrentflow,butitissmallerandbrieferbecausetherehasnotbeenenoughtimeformostoftheslowinactivationgatestoreopen.(B, C, andD areredrawnfrom http://www.physiologymodels.info/electrophysiology voltage-sensitive gate (activation gate) whose probability of being open increases with depolarization. However, unlike K+ channels, with maintained depolarization, Na+ channels open only at the onset of the depolarization and then remain closed. This suggests that Na+ channels have a second gate (inactivation gate) whose probability of being open goes down as the membrane is depolarized. Thus any Na+ current conducted by these channels will be transient (see
Fig. 5.6D ), because the same stimulus (depolarization) increases both the probabilities that the activation gate will open and that the inactivation gate will close. Note that the Na+ channel thus has two closed states, one in which the activation gate is closed, and the channel is said to be “closed,” and one in which the inactivation gate is closed, and the channel is referred to as “inactivated.” The reason the channel is called “inactivated” when the second gate closes is that once this gate closes, it will remain so until the membrane is repolarized. The activation gate, in contrast, can open and close at all membrane potentials, just with differing probabilities.
With the knowledge of the Na+ and K+ channel gating behavior just discussed, we can understand how the action potential is generated by the interaction of these channels (in the following, we assume that both gNa and gK change during the action potential). As stated previously, the action potential starts with a rapid increase in Na+ conductance (gNa;
Fig. 5.7 ). This increase in Na+ conductance reflects the opening of many Na+ channels in response to the depolarization. The open channels allow the influx of Na+ ions, and the effect of this current is to depolarize the membrane further. Note that this is a positive feedback loop, which accounts for the explosive nature of the action potential: the Na+ current depolarizes the membrane, which causes more Na+ channels to open, which in turn increases the Na+ current. In sum, the voltage-dependent opening of Na+ channels and the depolarizing action of the Na+ current account for the rising phase of the action potential.