Calciumdependent Action Potentials

Action potentials are not unique to neurons. Action potentials are also found in non-neuronal excitable cells, such as muscle cells (as we will see in Part III of this book), and even in single-celled animals. Figure 6-12 shows that the protozoan, Paramecium, can produce action potentials similar to those of nerve cells, except that the action potential results from influx of calcium ions rather than sodium ions as in the typical nerve action potential. The depolarizing upstroke of the action potential is caused by influx of positively charged calcium ions, rather than influx of sodium ions. As with sodium ions, the equilibrium potential for calcium ions (with a valence of +2) is positive, so if the membrane potential is negative and a calcium channel opens, there will be an influx of calcium into the cell. In the case of the sodium-dependent action potential, sodium channels activated by depolarization provide the basis for the regenerative all-or-none depolarizing phase of the action potential. Similarly, in the case of calcium-dependent action potentials, calcium channels that open upon depolarization underlie the depolarizing phase of the action potential. Depolarization opens calcium channels, which allow influx of positively

Figure 6-12 The single-celled protozoa, Paramecium, produces an action potential similar to a nerve action potential. (a) This diagram shows the recording configuration for intracellular recording. (b) The action potential elicited by an electrical stimulus (at the arrow). The action potential results from calcium influx through voltage-sensitive calcium channels.

Figure 6-12 The single-celled protozoa, Paramecium, produces an action potential similar to a nerve action potential. (a) This diagram shows the recording configuration for intracellular recording. (b) The action potential elicited by an electrical stimulus (at the arrow). The action potential results from calcium influx through voltage-sensitive calcium channels.

charged calcium ions, which in turn produces more depolarization and opens more calcium channels (see Figure 6-5 for the analogous situation with depolarization-activated sodium channels). The calcium-dependent action potential in Paramecium is also similar to nerve action potentials in that it serves a coordinating function: it regulates the direction of ciliary beating and thus the movement of the cell. Mutant paramecia that lack the ion channels underlying the calcium action potential are unable to reverse the direction of ciliary beating and thus are unable to swim backwards when they encounter noxious environmental stimuli. Because these mutants can only swim forward, they are called "pawn" mutants, after the chess piece that can only move forward. Thus, some of the basic molecular machinery for electrical signaling, one of the hallmarks of nervous system function, predates by far the origin of the first neuron. This suggests that neural signaling arose by the evolutionary modification of preexisting signaling mechanisms, found already in single-celled animals.

Voltage-dependent calcium channels are found in most neurons, and in some neurons, these voltage-activated calcium channels contribute significantly to the action potential. A comparison between the waveform of the sodium-dependent action potential and the waveform of an action potential with a component caused by calcium influx is shown in Figure 6-13. Often, the depolarization produced by calcium influx is slower and more sustained than the more spike-like action potential due to sodium and potassium channels alone. This is because the voltage-activated calcium channels commonly inactivate more slowly than voltage-activated sodium channels, so they produce a

without Ca2+ channels

Figure 6-13 Comparison between action potentials in neurons without a contribution from voltage-dependent calcium channels (a) and with a calcium component (b). The rising phase of the action potential on the bottom is produced by depolarization-activated sodium channels, and the dashed black line shows the expected time-course of the action potential in the absence of calcium channels. The prolonged plateau depolarization is caused by the opening of voltage-sensitive calcium channels.

without Ca2+ channels

Figure 6-13 Comparison between action potentials in neurons without a contribution from voltage-dependent calcium channels (a) and with a calcium component (b). The rising phase of the action potential on the bottom is produced by depolarization-activated sodium channels, and the dashed black line shows the expected time-course of the action potential in the absence of calcium channels. The prolonged plateau depolarization is caused by the opening of voltage-sensitive calcium channels.

more sustained influx of positive charge, and thus a more prolonged depolarization. In neurons with a calcium-dependent component, then, the action potential has a rapid upstroke caused by the opening of sodium channels, followed by a longer duration plateau phase caused by the voltage-dependent calcium channels.

The influx of calcium ions through voltage-dependent calcium channels has functional consequences beyond contributing to the action potential. The increase in the intracellular concentration of calcium that results from the influx is an important cellular signal that allows depolarization of a cell to be coupled to the triggering of internal cellular events. For example, we will see in Chapter 8 that an increase in intracellular calcium is the trigger for release of neurotransmitter from the presynaptic terminal when an action potential arrives at the synapticjunction between two neurons. Another important effect of internal calcium is the activation ofother kinds of ion channels. In addition to the potassium channels opened by depolarization, which we have discussed previously in this chapter, neurons frequently have potassium channels that are opened by an increase in internal calcium. Such calcium-activated potassium channels can contribute to action potential repolarization in neurons that have a calcium component in the action potential (e.g., Figure 6-13). As we have discussed earlier, an increase in potassium permeability accounts in part for the repolarizing phase of the action potential and produces the hyper-polarizing undershoot after repolarization. This increase in potassium permeability can be accomplished with voltage-activated potassium channels or with calcium-activated potassium channels. The activation scheme for calcium-activated potassium channels is summarized in Figure 6-14.

One important functional difference between voltage-activated and calcium-activated potassium channels is the amount of time the channels can remain open after the membrane potential has returned to its negative level at the end of the action potential. The action potential undershoot corresponds to the time after an action potential when the voltage-dependent potassium channels remain open, while sodium permeability has returned to rest; because the ratio pNa/pK is therefore smaller than the usual value, the membrane potential is driven even nearer to the potassium equilibrium potential than the normal resting potential. The period of hyperpolarization during the undershoot ends as the voltage-dependent potassium channels close in response to repolar-ization, which takes a few milliseconds or less. Calcium-activated potassium channels, however, remain open for as long as the intracellular calcium level remains elevated after the action potential. This can be hundreds of times longer than the undershoot produced by the voltage-dependent potassium channels, as shown in Figure 6-15. The longer-lasting hyperpolarization is called the afterhyperpolarization to distinguish it from the undershoot. The presence of an afterhyperpolarization requires both a significant calcium influx during the action potential (to produce an increase in internal calcium concentration) and significant numbers of calcium-activated potassium channels (to produce an increase in potassium permeability in response to the

Figure 6-14 Activation of potassium channels by internal calcium ions. (a) Upon depolarization, voltage-dependent calcium channels open and calcium ions enter the cell from the extracellular fluid. The calcium ions then bind to and open calcium-activated potassium channels, which allow potassium ions to exit from the cell. (b) A summary of the sequence of events leading to the activation of calcium-activated potassium channels.

Figure 6-14 Activation of potassium channels by internal calcium ions. (a) Upon depolarization, voltage-dependent calcium channels open and calcium ions enter the cell from the extracellular fluid. The calcium ions then bind to and open calcium-activated potassium channels, which allow potassium ions to exit from the cell. (b) A summary of the sequence of events leading to the activation of calcium-activated potassium channels.

increase in internal calcium). Not all neurons possess these requirements and thus not all neurons show prolonged afterhyperpolarizations. In neurons that have only a small component of calcium influx during a single action potential, afterhyperpolarizations may still be observed if the cell fires a rapid burst of action potentials because the internal calcium contributed by each action potential may sum temporally to reach the calcium level necessary to activate calcium-activated potassium channels. The afterhyperpolarization is important in determining the temporal patterning of action potentials, because the long period of increased potassium permeability makes it more difficult for the neuron to fire action potentials in a rapid series. In neurons that require a burst of several action potentials to initiate the afterhyperpolarization, the calcium-activated potassium channels can be important in terminating the burst. This can be a mechanism for timed bursts of action potentials separated by silent periods in neurons that control rhythmic events.

Fast time scale

Slow time scale

Resting potential

Fast time scale

Resting potential

1 Undershoot

\ (voltage-dependent

1 K+ channels)

______J

I /

5 msec

Undershoot (brief)

100 msec

Resting potential

Resting potential

Afterhyperpolarization (calcium-dependent K+ channels)

x Afterhyperpolarization (prolonged)

Figure 6-15 The time-course of the undershoot compared with the time-course of the afterhyperpolarization produced by calcium-activated potassium channels. (a) The action potential of a neuron with only voltage-dependent sodium and potassium channels. (b) The action potential of a neuron with voltage-dependent calcium channels and calcium-activated potassium channels in addition to the usual voltage-dependent sodium and potassium channels. The left traces in both (a) and (b) show the action potential on a fast time scale (milliseconds), while the right traces show the same action potentials on a slower time scale (hundreds of milliseconds).

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