Neurochemistry

Multiple neurochemical processes are involved in the synthesis, packaging, and release of neurotransmitters, and in the production and function of neurotransmitter receptors. Significantly, each of these biochemical steps represents a point of potential regulation of synaptic function and a site of possible age-related changes.

Most neurons produce and release one of several small molecules that serve as neurotransmitters, including acetylcholine, biogenic amines (dopamine, norepinephrine, epinephrine, histamine, or serotonin), or amino acids (glutamate, glycine, or gamma-aminobutyric acid). Many neurons also release one or more neuroactive peptides (neuropeptides), which provide additional modulation of signal transmission. Low levels of neuronal activity often result in release of only the small-molecule transmitter, whereas higher levels of activity result in the co-release of neuropeptides. Release of the neuropeptides may cease at very high levels of activity, however, since peptides must be delivered from the cell body and are replenished slowly. In contrast, synthesis and packaging of other neurotransmitters occurs more rapidly because the necessary synthetic enzymes are present within the cytoplasm in the region of the synapse. The release of neurotransmitters depends upon an increase in intracellular calcium that occurs with the depolarization (decrease in membrane potential) associated with the arrival of action potentials, regenerative waves of electrical activity that are the basis for signaling along neronal processes. Increased calcium leads to modification of vesicle-binding proteins, which facilitate the fusion of vesicles, membrane-bound packages in the cytoplasm, with the cell membrane and subsequent release of the vesicles' contents into the extracellular space.

After release, all neurotransmitters bind to neurotransmitter receptors and initiate changes in the postsynaptic neuron. It is the biochemical properties of the receptor protein, rather than that of the neurotransmitter itself, that determine the response of the postsynaptic cell. Each neurotransmitter binds to a different receptor, although multiple receptor types exist for several neurotransmitters, with each receptor initiating a different response in the target neuron. Functionally, neurotransmitter receptors fall into two groups, based on the mechanisms by which they alter the electrical activity of a neuron. Ionotropic receptors include an ion channel as part of their structure, and binding of the neurotransmitter results in immediate opening of that ion channel. Metabotropic receptors influence ion channels indirectly through activation of one of several second-messenger pathways. The three second-messenger systems that have been identified so far are similarly organized in that each includes a ligand-binding receptor domain coupled to a transducer that regulates the activity of an effector enzyme. The enzyme produces a second messenger that acts directly on one or more target proteins or activates additional, secondary effector enzymes. In addition to regulating ion channels, second-messenger systems may influence a variety of intracellular processes and elicit long-lasting changes in stimulated neurons.

Once a neurotransmitter has activated its receptors, it must be removed or destroyed rapidly in order to permit transmission of subsequent signals. Some neurotransmitters, regardless of type, simply diffuse from the synaptic cleft. Small-molecule neurotransmitters are also taken back up by presynaptic and postsynaptic neurons and by neighboring cells. One neurotransmitter, acetylcholine (ACh), is broken down rapidly by a membrane-bound enzyme in the region of the synapse. Neuroactive peptides are eliminated only by diffusion from the synaptic cleft and by proteolysis (degradation) by extracellular enzymes; thus they tend to have more sustained effects than small-molecule neurotransmitters.