The Na+ channels also have an automatic inactivating mechanism, which causes the channels to reclose rapidly even though the membrane is still depolarized (see Figure 11–30). The Na+ channels remain in this inactivated state, unable to reopen, until after the membrane potential has returned to its initial negative value. The time necessary for a sufficient number of Na+ channels to recover from inactivation to support a new action potential, termed the refractory period, limits
Figure 11–29 Structural models of voltage-gated Na+ channels. (A) The channel in animal cells is built from a single polypeptide chain that contains four homologous domains. Each domain contains two transmembrane α helices (green) that surround the central ion-conducting pore. They are separated by sequences (blue) that form the selectivity filter. Four α additional helices (gray and red) in each domain constitute the voltage sensor. The S4 helices (red) are unique in that they contain an abundance of positively charged arginines. An inactivation gate that is part of a flexible loop connecting the third and fourth domains acts as a plug that obstructs the pore in the channel’s inactivated state, as shown in Figure 11–30. (B) Side and top views of a homologous bacterial channel protein showing its arrangement within the membrane. (C) A cross section of the pore domain of the channel shown in (B) shows lateral portals, through which the central cavity is accessible from the hydrophobic core of the lipid bilayer. In the crystals, lipid acyl chains were found to intrude into the pore. These lateral portals are large enough to allow entry of small, hydrophobic, pore-blocking drugs that are commonly used as anesthetics and block ion conductance. (PDB code: 3RVZ.)
Figure 11–30 Na+ channels and an action potential. (A) An action potential is triggered by a brief pulse of current, which (B) partially depolarizes the membrane, as shown in the plot of membrane potential versus time. The green curve shows how the membrane potential would have simply relaxed back to the resting value after the initial depolarizing stimulus if there had been no voltage-gated Na+ channels in the membrane. The red curve shows the course of the action potential that is caused by the opening and subsequent inactivation of voltage-gated Na+ channels. The states of the Na+ channels are indicated in (B). The membrane cannot fire a second action potential until the Na+ channels have returned from the inactivated to the closed conformation; until then, the membrane is refractory to stimulation. (C) The three states of the Na+ channel. When the membrane is at rest (highly polarized), the closed conformation of the channel has the lowest free energy and is therefore most stable; when the membrane is depolarized, the energy of the open conformation is lower, so the channel has a high probability of opening. But the free energy of the inactivated conformation is lower still; therefore, after a randomly variable period spent in the open state, the channel becomes inactivated. Thus, the open conformation corresponds to a metastable state that can exist only transiently when the membrane depolarizes (Movie 11.10).
the repetitive firing rate of a neuron. The cycle from initial stimulus to the return to the original resting state takes a few milliseconds or less. The Na+ channel can therefore exist in three distinct states—closed, open, and inactivated—which contribute to the rise and fall of the action potential (Figure 11–30).
This description of an action potential applies only to a small patch of plasma membrane. The self-amplifying depolarization of the patch, however, is sufficient to depolarize neighboring regions of membrane, which then go through the same cycle. In this way, the action potential sweeps like a wave from the initial site of depolarization over the entire plasma membrane, as shown in Figure 11–31.
The Use of Channelrhodopsins Has Revolutionized the Study of Neural Circuits