its concentration across the membrane — due to diffusion and electric field forces created by sodium-potassium pumps — we find that the resting membrane potential is due mostly to the resting potassium conductance. Opening sodium channels that
depolarize the inside of the neuron change all this drastically.
Controlling ion permeability: Gated channels
Earlier in this chapter, I explain that ion channels can be gated either by ligands (neurotransmitters) or voltage. Gating changes the channel’s state from closed to open, or vice versa. Gated channels are at the core of how neurons integrate and process inputs, and how they communicate with other neurons (or, as neurobiologists always say, “No neuron is an island”). Neurons receive messages in the form of neurotransmitters through ligand-gated channels on their dendrites, soma, and, in some cases, axon. These inputs are excitatory if the receptors flux sodium ions, inhibitory if they flux potassium or chloride.
Opening channels changes the voltage across the neurons membrane by the flow of ions. We use the Goldman–Hodgkin–Katz equation to calculate the membrane potential that results. If the neuronal membrane potential becomes sufficiently less negative (depolarized), the effect may be to open voltage-gated ion channels. Two of the most important voltage-gated ion channels are those of the sodium and potassium channels that lead to the action potential, an all-or-nothing spike of voltage that serves as the basic unit of electrical signaling in neurons.
Making Spikes with Sodium and Potassium Channels
Imagine a neuron at its resting potential of about –65 mV. Some other neuron that is presynaptic to this one releases glutamate, which binds to the first neuron’s excitatory glutamate receptors. This process opens a glutamate receptor, which passes a (mostly) sodium current. Sodium rushes into the cytoplasm from outside the neuron and depolarizes it, reducing potential across the membrane from –65 mV to around –20 mV. This is above the threshold for voltage-gated sodium channels in the first neuron’s membrane, which are now open.
Getting back to resting potential
Opening voltage-gated sodium channels, which increase the flow of sodium into the cell, further depolarizes the cell. This opens any other nearby voltage-dependent sodium channels. The situation is one of typical
positive feedback in which the neuron is increasingly being driven toward the sodium equilibrium potential (approximately +55 mV, depending on the cell, from the Nernst equation). This amplification causes the neuron to remain stuck in this depolarized condition, unless something happens to get it back to its resting potential. Two things can work to do this:
Sodium channels close themselves.
Voltage-dependent potassium channels open.
In this chapter, I cover voltage-dependent sodium channels as though they only exist in two states — open or closed — but that isn’t quite right. A third state exists: When the neuron is in the resting state, the voltage-dependent sodium channels are in a state that is
closed, but capable of opening (meaning they can be opened by voltage). When the membrane potential crosses the threshold, the channels transition to the
open state. The third state occurs in less than one millisecond after the channels open. A mechanism within the channel causes the voltage-dependent channels to close themselves and transition to a state that is
closed, but not immediately capable of reopening. That is, even though the membrane voltage may continue to remain above their opening threshold, they won’t open again. This process is called
inactivation. The transition to this third, closed state causes the neuron to
repolarize (meaning return to the resting potential), along with potassium channel activity, which we discuss in the next section. Milliseconds after the neuron repolarizes, the voltage-dependent sodium channels transition from the inactivated state back to the original closed state. Then the cycle can begin again.
Voltage-dependent channels
The sudden opening and then closing of many voltage-dependent sodium channels produces an action potential, or spike — sharp voltage change across the cell’s membrane.
If you do a computer simulation of the action of voltage-dependent sodium channels using their known kinetics, the simulated action potential lasts longer than actual spikes in most real neurons. The reason is that
voltage-dependent potassium channels also exist
, and they’re almost always near voltage-dependent sodium channels. (They also open when the neuron is depolarized, but more slowly than the sodium channels.) When these voltage-dependent potassium channels open, potassium flows out of the cell, which drives the membrane potential toward the potassium equilibrium potential around –75 mV. This shortens the duration of the action potential because opening potassium channels repolarizes the cell more rapidly than closing the voltage-dependent sodium channels.
Reaching action potential
The voltage-dependent potassium channels also close on their own after opening, but much more slowly than the sodium channels. A lingering potassium current remains after each action potential that makes firing another action potential more difficult, because a subsequent depolarizing input must fight this hyperpolarizing potassium current.
The period immediately following an action potential when it’s more difficult or impossible to elicit a second action potential is called the refractory period. It has two phases:
Absolute refractory period: The absolute refractory period is when the sodium channels are in the inactivated state. In this state no additional action potential can be elicited, no matter how strong the depolarizing input.
Relative refractory period: The relative refractory period is when the potassium channels are still open, but the sodium channels have transition from closed, inactivatable, to closed, activatable. Another spike is hard — but not impossible — to produce because of the relative refractory period after the sodium channel transitions (from the inactivated to the closed state) and potassium currents are lingering.
See how these events play out in Figure 3-2.
Figure 3-2: Event sequence underlying action potential, including voltage across the membrane (V), sodium channel conductance (gNa), and potassium channel conductance (gK).
The trace in Figure 3-2 labeled “V” is the membrane potential, and the scale for this trace is on the left. At the start of the plot, the membrane potential is at the resting level, or about –65 mV. As sodium channels open, the potential moves toward the sodium equilibrium potential (although it may not actually reach this 55 mV level). The membrane potential then declines to a level below the resting potential, and then finally returns to the resting potential.
The other two traces in Figure 3-2 show the sodium and potassium permeabilities that control this membrane potential. The action potential (voltage, membrane potential trace) is caused by any input that depolarizes the cell enough to open the voltage-dependent sodium channels. The permeability (a biophysical term corresponding to electrical conductance) of the sodium channels is given by the gNa trace, whose values (conductance) correspond to the axis on the right. This conductance is nearly zero at the resting potential, rises to a maximum near the membrane potential peak, and then returns to zero through
