The membranes of neurons contain two types of channels defined on the basis of the mechanisms controlling their gating (opening and closing): voltage-gated and ligand-gated channels (Figure 21–2A and B). Voltage-gated channels respond to changes in the membrane potential of the cell. The voltage-gated sodium channel described in Chapter 14 for the heart is an example of this type of channel. In nerve cells, these channels are highly concentrated on the initial segment of the axon (Figure 21–1), which initiates the all-or-nothing fast action potential, and along the length of the axon where they propagate the action potential to the nerve terminal. There are also many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment, which act on a much slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit further action potential discharge. Plant and animal toxins that target various voltage-gated ion channels have been invaluable for studying the functions of these channels (see Box: Natural Toxins: Tools for Characterizing Ion Channels; Table 21–1).
FIGURE 21–2 Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sensor component of the protein controls the gating (broken arrow) of the channel. B shows a ligand-gated channel in which the binding of the neurotransmitter to the ionotropic channel receptor controls the gating (broken arrow) of the channel. C shows a G protein-coupled (metabotropic) receptor, which, when bound, activates a heterotrimeric G protein. D and E show two ways metabotropic receptors can regulate ion channels. The activated G protein can interact directly to modulate an ion channel (D) or the G protein can activate an enzyme that generates a diffusible second messenger (E), eg, cAMP, which can interact with the ion channel or can activate a kinase that phosphorylates and modulates a channel.
Evolution is tireless in the development of natural toxins. A vast number of variations are possible with even a small number of amino acids in peptides, and peptides make up only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus includes over 3000 different species. Each species kills or paralyzes its prey with a venom that contains 50–200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant spe-cies with toxic (or therapeutic) substances are referred to in several other chapters of this book. Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small percentage of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion channels, but a number of very useful toxins block ligand-gated ion channels receptors. Table 21–1 lists some of the toxins most commonly used in research, their mode of action, and their source.
Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptor. The first class is referred to as ligand-gated channels, or ionotropic receptors. These receptors consist of multiple subunits, and binding of the neurotransmitter ligand directly opens the channel, which is an integral part of the receptor complex (see Figure 22–6). These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS (see following text).