Figure 11–38 a model for the structure of the skeletal muscle acetylcholine receptor. (A) Five homologous subunits (α, α, β, γ, δ) combine to form a transmembrane pore. Both of the α subunits contribute an acetylcholinebinding site nestled between adjoining subunits. (B) The pore is lined by a ring of five transmembrane α helices, one contributed by each subunit (just the two α subunits are shown). In its closed conformation, the pore is occluded by the hydrophobic side chains of five leucines (green), one from each α helix, which form a gate near the middle of the lipid bilayer. When acetylcholine binds to both α subunits, the channel undergoes a conformational change that opens the gate by an outward rotation of the helices containing the occluding leucines. Negatively charged side chains (indicated by the “–“ signs) at either end of the pore ensure that only positively charged ions pass through the channel. (PDB code: 2BG9.) by blocking the acetylcholine receptors on skeletal muscle cells with curare, a plant-derived drug that was originally used by South American Indians to make poison arrows. Most drugs used to treat insomnia, anxiety, depression, and schizophrenia exert their effects at chemical synapses, and many of these act by binding to transmitter-gated channels. Barbiturates, tranquilizers such as Valium, and sleeping pills such as Ambien, for example, bind to GABA receptors, potentiating the inhibitory action of GABA by allowing lower concentrations of this neurotransmitter to open Cl– channels. Our increasing understanding of the molecular biology of ion channels should allow us to design a new generation of psychoactive drugs that will act still more selectively to alleviate the miseries of mental illness.
In addition to ion channels, many other components of the synaptic signaling machinery are potential targets for psychoactive drugs. As mentioned earlier, after release into the synaptic cleft, many neurotransmitters are cleared by reuptake mechanisms mediated by Na+-driven symports. Inhibiting such transporters prolongs the effect of the neurotransmitter, thereby strengthening synaptic transmission. Many antidepressant drugs, including Prozac, inhibit the reuptake of serotonin; others inhibit the reuptake of both serotonin and norepinephrine.
Ion channels are the basic molecular units from which neuronal devices for signaling and computation are built. To provide a glimpse of how sophisticated these devices can be, we consider several examples that demonstrate how the coordinated activities of groups of ion channels allow you to move, feel, and remember.
Neuromuscular Transmission Involves the Sequential Activation of Five Different Sets of Ion Channels
The following process, in which a nerve impulse stimulates a muscle cell to contract, illustrates the importance of ion channels to electrically excitable cells. This apparently simple response requires the sequential activation of at least five different sets of ion channels, all within a few milliseconds (Figure 11–39).
1. The process is initiated when a nerve impulse reaches the nerve terminal and depolarizes the plasma membrane of the terminal. The depolarization transiently opens voltage-gated Ca2+ channels in this presynaptic membrane. As the Ca2+ concentration outside cells is more than 1000 times
Figure 11–39 The system of ion channels at a neuromuscular junction.
These gated ion channels are essential for the stimulation of muscle contraction by a nerve impulse. The various channels are numbered in the sequence in which they are activated, as described in the text.
greater than the free Ca2+ concentration inside, Ca2+ flows into the nerve terminal. The increase in Ca2+ concentration in the cytosol of the nerve terminal triggers the local release of acetylcholine by exocytosis into the synaptic cleft.
2.