Signaling at Synapses Usually Is Terminated by Degradation or Reuptake of Neurotransmitters

Following their release from a presynaptic cell, neurotrans-mitters must be removed or destroyed to prevent continued stimulation of the postsynaptic cell. Signaling can be terminated by diffusion of a transmitter away from the synaptic cleft, but this is a slow process. Instead, one of two more rapid mechanisms terminates the action of neurotransmitters at most synapses.

Signaling by acetylcholine is terminated when it is hy-drolyzed to acetate and choline by acetylcholinesterase, an enzyme localized to the synaptic cleft. Choline released in this reaction is transported back into the presynaptic axon terminal by a Na+/choline symporter and used in synthesis of more acetylcholine. The operation of this transporter is similar to that of the Na+-linked symporters used to transport glucose into cells against a concentration gradient (see Figure 7-21).

With the exception of acetylcholine, all the neurotrans-mitters shown in Figure 7-41 are removed from the synaptic cleft by transport into the axon terminals that released them. Thus these transmitters are recycled intact, as depicted in Figure 7-42 (step 5). Transporters for GABA, norepineph-rine, dopamine, and serotonin were the first to be cloned and studied. These four transport proteins are all Na+-linked symporters. They are 60-70 percent identical in their amino acid sequences, and each is thought to contain 12 transmembrane a helices. As with other Na+ symporters, the movement of Na+ into the cell down its electrochemical gradient provides the energy for uptake of the neurotransmit-ter. To maintain electroneutrality, Cl_ often is transported via an ion channel along with the Na+ and neurotransmitter.

▲ FIGURE 7-43 Synaptic vesicles in the axon terminal near the region where neurotransmitter is released. In this longitudinal section through a neuromuscular junction, the basal lamina lies in the synaptic cleft separating the neuron from the muscle membrane, which is extensively folded. Acetylcholine receptors are concentrated in the postsynaptic muscle membrane at the top and part way down the sides of the folds in the membrane. A Schwann cell surrounds the axon terminal. [From J. E. Heuser and T Reese, 1977, in E. R. Kandel, ed., The Nervous System, vol. 1, Handbook of Physiology, Williams & Wilkins, p. 266.]

▲ FIGURE 7-44 Sequential activation of gated ion channels at a neuromuscular junction. Arrival of an action potential at the terminus of a presynaptic motor neuron Induces opening of voltage-gated Ca2+ channels (step Ml ) and subsequent release of acetylcholine, which triggers opening of the ligand-gated acetylcholine receptors In the muscle plasma membrane (step 12 ). The resulting Influx of Na+ produces a localized depolarization of the membrane, leading to opening of voltage-gated Na+ channels and generation of an action potential (step |3| ). When the spreading depolarization reaches T tubules, It Is sensed by voltage-gated Ca2+ channels In the plasma membrane. This leads to opening of Ca2+-release channels In the sarcoplasmic reticulum membrane, releasing stored Ca2+ Into the cytosol (step |4l ). The resulting rise In cytosolic Ca2+ causes muscle contraction by mechanisms discussed In Chapter 19.

The nicotinic acetylcholine receptor, which is expressed in muscle cells, is a ligand-gated channel that admits both K+ and Na+. The effect of acetylcholine on this receptor can be determined by patch-clamping studies on isolated outside-out patches of muscle plasma membranes (see Figure 7-17c). Such measurements have shown that acetylcholine causes opening of a cation channel in the receptor capable of transmitting 15,000-30,000 Na+ or K+ ions per millisecond. However, since the resting potential of the muscle plasma membrane is near EK, the potassium equilibrium potential, opening of acetylcholine receptor channels causes little increase in the efflux of K+ ions; Na+ ions, on the other hand, flow into the muscle cell driven by the Na+ electrochemical gradient.

The simultaneous increase in permeability to Na+ and K+ ions following binding of acetylcholine produces a net depolarization to about — 15 mV from the muscle resting potential of —85 to —90 mV. As shown in Figure 7-44, this localized depolarization of the muscle plasma membrane triggers opening of voltage-gated Na+ channels, leading to generation and conduction of an action potential in the muscle cell surface membrane by the same mechanisms described previously for neurons. When the membrane depolarization reaches T tubules, specialized invaginations of the plasma membrane, it affects Ca2+ channels in the plasma membrane apparently without causing them to open. Somehow this causes opening of adjacent Ca2+-release channels in the sar-coplasmic reticulum membrane. The subsequent flow of stored Ca2+ ions from the sarcoplasmic reticulum into the cytosol raises the cytosolic Ca2+ concentration sufficiently to induce muscle contraction.

Careful monitoring of the membrane potential of the muscle membrane at a synapse with a cholinergic motor neuron has demonstrated spontaneous, intermittent, and random «2-ms depolarizations of about 0.5-1.0 mV in the absence of stimulation of the motor neuron. Each of these depolarizations is caused by the spontaneous release of acetylcholine from a single synaptic vesicle. Indeed, demonstration of such spontaneous small depolarizations led to the notion of the quantal release of acetylcholine (later applied to other neurotransmitters) and thereby led to the hypothesis of vesicle exocytosis at synapses. The release of one acetyl-choline-containing synaptic vesicle results in the opening of about 3000 ion channels in the postsynaptic membrane, far short of the number needed to reach the threshold depolarization that induces an action potential. Clearly, stimulation of muscle contraction by a motor neuron requires the nearly simultaneous release of acetylcholine from numerous synap-tic vesicles.

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