As we have discussed, electrical pulses transmit signals along neurons, but signals are transmitted between neurons and other excitable cells mainly by chemical signals. Synapses are the junctions where presynaptic neurons release these chemical signals, or neurotransmitters, which then act on postsynaptic target cells (see Figure 22-3). A target cell may be another neuron, a muscle, or a gland cell. Communication at chemical synapses usually goes in only one direction: pre- to postsynaptic cell.

Arrival of an action potential at an axon terminus in a presynaptic cell leads to opening of voltage-sensitive Ca²⁺ plasma membrane channels and an influx of Ca²⁺, causing a localized rise in the cytosolic Ca²⁺ concentration in the axon terminus. In turn, the rise in Ca²⁺ triggers fusion of small (40–50 nm) neurotransmitter-containing synaptic vesicles with the plasma membrane, releasing neurotransmitters into the synaptic cleft, the narrow space separating the presynaptic from the postsynaptic cell. The membrane of the postsynaptic cell is located within approximately 20 nm of the presynaptic membrane, reducing the distance the neurotransmitter must diffuse.

Neurotransmitters—small, water-soluble molecules such as glutamate (excitatory) or gamma-amino butyric acid (GABA, inhibitory)—bind to receptors on the postsynaptic cell that, in turn, induce localized changes in the potential across its plasma membrane. If the membrane potential becomes less negative—that is, becomes depolarized—an action potential will tend to be induced in the postsynaptic cell. Such synapses are excitatory, and in general involve the opening of Na⁺ channels in the postsynaptic plasma membrane. In contrast, in an inhibitory synapse, binding of the neurotransmitter to a receptor on the postsynaptic cell causes hyperpolarization of the plasma membrane—generation of a more inside-negative potential. Typically, hyperpolarization is the result of opening of Cl^– or K⁺ channels in the postsynaptic plasma membrane, which tends to hinder generation of an action potential.

Neurotransmitter receptors fall into two broad classes: ligand-gated ion channels, which open immediately upon neurotransmitter binding, and metabotropic G protein–coupled receptors (GPCRs). Neurotransmitter binding to a GPCR induces the opening or closing of a separate ion-channel protein over a period of seconds to minutes. These “slow” neurotransmitter receptors were discussed in Chapter 15 along with GPCRs that bind different types of ligands and modulate the activity of cytosolic proteins other than ion channels. In the central nervous system, glutamate and GABA bind primarily to ionotropic receptors to mediate excitation and inhibition, respectively, while neuromodulators like serotonin and dopamine bind to metabotropic receptors. In the peripheral nervous system, the main neurotransmitters are acetylcholine and norepinephrine (also called noradrenaline), both of which are also expressed in the central nervous system.

The duration of the neurotransmitter signal depends on the amount of transmitter released by the presynaptic cell, which in turn depends on the amount of transmitter that had been stored as well as the frequency of action potentials arriving at the synapse. The duration of the signal also depends on how rapidly any unbound neurotransmitter is degraded in the synaptic cleft or transported back into the presynaptic cell. Presynaptic cell plasma membranes, as well as glia, contain transporter proteins that pump neurotransmitters across the plasma membrane back into the cell, thus keeping the extracellular concentrations of transmitter low.

In this section we focus first on how synapses form and how they control the regulated secretion of neurotransmitters in the context of the basic principles of vesicular trafficking outlined in Chapter 14. Next we look at the mechanisms that limit the duration of the synaptic signal, and how neurotransmitters are received and interpreted by the postsynaptic cell.