The first step in synaptic transmission is the synthesis and storage of neurotransmitters. There are two broad categories of neurotransmitters. Small-molecule neurotransmitters are synthesized locally within the axon terminal. Some of the precursors necessary for the synthesis of these molecules are taken up by selective transporters on the membrane of the terminal. Others are byproducts of cellular processes that take place within the neuron itself and are thus readily available. The enzymes necessary to catalyze an interaction among these precursors are usually produced in the cell body and transported to the terminal by slow axonal transport.

Acetylcholine (ACh), is an example of an excitatory small-molecule neurotransmitter. This important, well-studied neurotransmitter, made up of choline and acetate, is found at various locations throughout the central and peripheral nervous systems and at all neuromuscular junctions. The synthesis of ACh requires the enzyme choline actyltransferase and, like all small-molecule neurotransmitters, takes place within the nerve terminal.

Neuropeptides are the second category of neurotransmitters. These messengers differ from small-molecule neurotransmitters in both size and in the way that they are synthesized. Neuropeptides generally range from 3 to 36 amino acids in length, and are thus larger than small-molecule neurotransmitters. Also, neuropeptides must made in the cell body because their synthesis requires peptide bond formation. This process is a great deal more involved than the simple enzymatic reactions involved in making smaller neurotransmitters.

The synthesis of a neuropeptide is very much like the synthesis of any secretory protein made by the cell. First, within the cell nucleus, gene transcription takes place, during which a specific peptide-coding sequence of DNA is used as a template to construct a corresponding strand of messenger RNA. The mRNA then travels to a ribosome, where the process of translation begins. During translation, the sequence of nucleotides that make up the mRNA act as a code to string together a corresponding sequence of amino acids that will eventually become the neuropeptide needed at the terminal. Before this molecule can be transported to the terminal for release into the synaptic cleft, it must be processed in the endoplasmic reticulum (ER), packaged in the golgi apparatus, and transported in storage vesicles down the axon to the terminal.

The endogenous opioids, a large family of neuropeptides that act as natural analgesics, provide a good example of how post-translational processing of just one precursor molecule can result in a whole spectrum of different, but related, neurotransmitters. Selective cleaving and splicing of each just three precursor molecules results in the production of the various opioids included in this family of neurotransmitters.

Once they are synthesized, neurotransmitters, both small molecules and neuropeptides, are stored in vesicles within the axon terminal until an action potential arrives and they are released. Most small-molecule neurotransmitters are stored in small vesicles that range from 40 to 60 nm in diameter and, in electron micrographs, appear to have clear centers. The vesicles that store neuropeptides are larger, ranging from 90 to 250 nm in diameter. These vesicles appear dark and electron-dense in electron micrographs. For a table of small molecule neurotransmitters and their site of synthesis, go to http://web.indstate.edu/thcme/mwking/nerves.html#table