The Acetylcholine Receptors at the Neuromuscular Junction Are Excitatory Transmitter-Gated Cation Channels
A well-studied example of a transmitter-gated ion channel is the acetylcholine receptor of skeletal muscle cells. This channel is opened transiently by acetylcholine released from the nerve terminal at a neuromuscular junction—the specialized chemical synapse between a motor neuron and a skeletal muscle cell (Figure 11–37). This synapse has been intensively investigated because it is readily accessible to electrophysiological study, unlike most of the synapses in the central nervous system, that is, the brain and spinal cord in vertebrates. Moreover, the acetylcholine receptors are densely packed in the muscle cell plasma membrane at a neuromuscular junction (about 20,000 such receptors per μm2), with relatively few receptors elsewhere in the same membrane.
The receptors are composed of five transmembrane polypeptides, two of one kind and three others, encoded by four separate genes (Figure 11–38A). The four genes are strikingly similar in sequence, implying that they evolved from a single ancestral gene. The two identical polypeptides in the pentamer each contribute one acetylcholine-binding site. When two acetylcholine molecules bind to the pentameric complex, they induce a conformational change that opens the channel. With ligand bound, the channel still flickers between open and closed states, but now it has a 90% probability of being open. This state continues—with acetylcholine binding and unbinding—until hydrolysis of the free acetylcholine by the enzyme acetylcholinesterase lowers its concentration at the neuromuscular junction sufficiently. Once freed of its bound neurotransmitter, the acetylcholine receptor reverts to its initial resting state. If the presence of acetylcholine persists for a prolonged time as a result of excessive nerve stimulation, the channel inactivates. Normally, the acetylcholine is rapidly hydrolyzed and the channel closes within about 1 millisecond, well before significant desensitization occurs. Desensitization would occur after about 20 milliseconds in the continued presence of acetylcholine.
The five subunits of the acetylcholine receptor are arranged in a ring, forming a water-filled transmembrane channel that consists of a narrow pore through the lipid bilayer, which widens into vestibules at both ends. Acetylcholine binding opens the channel by causing the helices that line the pore to rotate outward, thus disrupting a ring of hydrophobic amino acids that blocks ion flow in the closed state. Clusters of negatively charged amino acids at either end of the pore help to exclude negative ions and encourage any positive ion of diameter less than 0.65 nm to pass through (Figure 11–38B). The normal through-traffic consists chiefly of Na+ and K+, together with some Ca2+. Thus, unlike voltage-gated cation channels, such as the K+ channel discussed earlier, there is little selectivity among cations, and the relative contributions of the different cations to the current through the channel depend chiefly on their concentrations and on the electrochemical driving forces. When the muscle cell membrane is at its resting potential, the net driving force for K+ is near zero, since the voltage gradient nearly balances the K+ concentration gradient across the membrane (see Panel 11–1, p. 616). For Na+, in contrast, the voltage gradient and the concentration gradient both act in the same direction to drive the ion into the cell. (The same is true for Ca2+, but the
Figure 11–37 a low-magnification scanning electron micrograph of a neuromuscular junction in a frog. The termination of a single axon on a skeletal muscle cell is shown. (From J. Desaki and