Voltage-gated ion channels that are selectively permeable to each of the major physiological ionsNa⁺, K⁺, Ca²⁺, and Cl^-have now been discovered (Figure 4.4A-D). Indeed, many different genes have been discovered for each type of voltage-gated ion channel. For example, 10 human Na⁺ channel genes have been identified. This finding was unexpected because Na⁺ channels from many different cell types have similar functional properties, consistent with their origin from a single gene. It is now clear, however, that all of these Na⁺ channel genes produce proteins that differ in their structure, function, and distribution in specific tissues. For example, in addition to the rapidly inactivating Na⁺ channels discovered by Hodgkin and Huxley in squid axon, a voltage-sensitive Na⁺ channel that does not inactivate has been identified in mammalian axons. As might be expected, this channel gives rise to action potentials of long duration and is one of the targets of local anesthetics such as benzocaine and lidocaine.

Other electrical responses in neurons are due to the activation of voltage-gated Ca²⁺ channels (Figure 4.4B). In some neurons, voltage-gated Ca²⁺ channels give rise to action potentials in much the same way as voltage-sensitive Na⁺ channels. In many other neurons, Ca²⁺ channels can control the shape of action potentials generated primarily by Na⁺ conductance changes. By affecting intracellular Ca²⁺ concentrations, the activity of Ca²⁺ channels regulates an enormous range of biochemical processes within cells (see Chapter 8). Perhaps the most important of the processes regulated by voltage-sensitive Ca²⁺ channels is the release of neurotransmitters at synapses (see Chapter 5). Given these crucial functions, it is perhaps not surprising that 16 different Ca²⁺ channel genes have been identified. Like Na⁺ channels, different Ca²⁺ channels differ in their activation and inactivation properties, allowing subtle variations in both electrical and chemical signaling processes mediated by Ca²⁺. As a result, drugs that block voltage-gated Ca²⁺ channels are especially valuable in treating a variety of conditions ranging from heart disease to anxiety disorders.

The largest and most diverse class of voltage-gated ion channels are the K⁺ channels (Figure 4.4C). Nearly 100 K⁺ channel genes are now known, and these fall into several distinct groups that differ substantially in their gating properties (Figure 4.5). Some take minutes to inactivate, as in the case of squid axon K⁺ channels studied by Hodgkin and Huxley. Others inactivate within milliseconds, as is typical of most voltage-gated Na⁺ channels. These properties influence the duration and rate of action potential firing, with important consequences for axonal conduction and synaptic transmission. Perhaps the most important function of K⁺ channels is the part they play in generating the resting membrane potential (see Chapter 2). At least two families of K⁺ channels that are open at hyperpolarized membrane potentials contribute to setting the resting membrane potential.

Finally, several types of voltage-gated Cl^- channel also have been identified (see Figure 4.4D). These channels are present in every type of neuron, where they control excitability, contribute to the resting membrane potential, and help regulate cell volume.