Transmitter-gated ion channels differ from one another in several important ways. First, as receptors, they have highly selective binding sites for the neurotransmitter that is released from the presynaptic nerve terminal. Second, as channels, they are selective in the type of ions that they let pass across the plasma membrane; this determines the nature of the postsynaptic response. Excitatory neurotransmitters open cation channels, causing an influx of Na+, and in many cases Ca2+, that depolarizes the postsynaptic membrane toward the threshold potential for firing an action potential. Inhibitory neurotransmitters, by contrast, open either Cl– channels or K+ channels, and this suppresses firing by making it harder for excitatory neurotransmitters to depolarize the postsynaptic membrane. Many transmitters can be either excitatory or inhibitory, depending on where they are released, what receptors they bind to, and the ionic conditions that they encounter. Acetylcholine, for example, can either excite or inhibit, depending on the type of acetylcholine receptors it binds to. Usually, however, acetylcholine, glutamate, and serotonin are used as excitatory transmitters, and γ-aminobutyric acid (GABA) and glycine are used as inhibitory transmitters. Glutamate, for instance, mediates most of the excitatory signaling in the vertebrate brain.
We have already discussed how the opening of Na+ or Ca2+ channels depolarizes a membrane. The opening of K+ channels has the opposite effect because the K+ concentration gradient is in the opposite direction—high concentration inside the cell, low outside. Opening K+ channels tends to keep the cell close to the equilibrium potential for K+, which, as we discussed earlier, is normally close to the resting membrane potential because at rest K+ channels are the main type of channel that is open. When additional K+ channels open, it becomes harder to drive the cell away from the resting state. We can understand the effect of opening Cl– channels similarly. The concentration of Cl– is much higher outside the cell than inside (see Table 11–1, p. 598), but the membrane potential opposes its influx. In fact, for many neurons, the equilibrium potential for Cl– is close to the resting potential—or even more negative. For this reason, opening Cl– channels tends to buffer the membrane potential; as the membrane starts to depolarize, more negatively charged Cl– ions enter the cell and counteract the depolarization. Thus, the opening of Cl– channels makes it more difficult to depolarize the membrane and hence to excite the cell. Some powerful toxins act by blocking the action of inhibitory neurotransmitters: strychnine, for example, binds to glycine receptors and prevents their inhibitory action, causing muscle spasms, convulsions, and death.
However, not all chemical signaling in the nervous system operates through these ionotropic ligand-gated ion channels. In fact, most neurotransmitter molecules that are secreted by nerve terminals, including a large variety of neuropeptides, bind to metabotropic receptors, which regulate ion channels only indirectly through the action of small intracellular signal molecules (discussed in Chapter 15). All neurotransmitter receptors fall into one or other of these two major classes—ionotropic or metabotropic—on the basis of their signaling mechanisms: 1.
Ionotropic receptors are ion channels and feature at fast chemical synapses. Acetylcholine, glycine, glutamate, and GABA all act on transmitter-gated ion channels, mediating excitatory or inhibitory signaling that is generally immediate, simple, and brief.
2.
Metabotropic receptors are G-protein-coupled receptors (discussed in Chapter 15) that bind to all other neurotransmitters (and, confusingly, also acetylcholine, glutamate, and GABA). Signaling mediated by ligand-binding to metabotropic receptors tends to be far slower and more complex than that at ionotropic receptors, and longer-lasting in its consequences.