13: Neurotransmitters

Introduction

• A Chemical Messenger Must Meet Four Criteria to Be Considered a Neurotransmitter

• Only a Few Small-Molecule Substances Act as Transmitters

  • Acetylcholine

  • Biogenic Amine Transmitters

  • Catecholamine Transmitters

  • Serotonin

  • Histamine

  • Amino Acid Transmitters

  • ATP and Adenosine

• Small-Molecule Transmitters Are Actively Taken Up into Vesicles

• Many Neuroactive Peptides Serve as Transmitters

• Peptides and Small-Molecule Transmitters Differ in Several Ways

• Peptides and Small-Molecule Transmitters Coexist and Can Be Co-released

• Removal of Transmitter from the Synaptic Cleft Terminates Synaptic Transmission

• An Overall View

Chemical synaptic transmission can be divided into four steps—(1) synthesis and storage of a transmitter substance, (2) release of the transmitter, (3) interaction of the transmitter with receptors at the postsynaptic membrane, and (4) removal of the transmitter from the synaptic cleft. In the previous chapter we considered steps 2 and 3: the release of transmitters and how they interact with postsynaptic receptors. We now turn to the initial and final steps of chemical synaptic transmission: the synthesis of transmitter molecules and their removal from the synaptic cleft after synaptic action.

A Chemical Messenger Must Meet Four Criteria to Be Considered a Neurotransmitter

Before considering the biochemical processes involved in synaptic transmission, it is important to make clear what is meant by a chemical transmitter. The concept is empirical rather than logical and has changed over the years with increased understanding of synaptic transmission.

The concept that nerve stimulation led to release of chemical signals was elaborated as early as 1905 by the physiologist John Newport Langley, who demonstrated that adrenomedullary extracts elicited tissue responses comparable to sympathetic nerve stimulation. However, Thomas Renton Elliott is generally credited with the first experimental evidence of chemical neurotransmission in his observations that the physiological effects of sympathetic nerve stimulation were due to release of adrenaline. In 1921 Otto Loewi demonstrated the release of acetylcholine (ACh) from vagus nerve terminals in frog hearts. Henry Dale extended Loewi's work on ACh, later sharing the Nobel Prize with Loewi. In 1946 Ulf von Euler reported further work on adrenergic transmission. The terms cholinergic and adrenergic were introduced to indicate that a neuron makes and releases ACh or norepinephrine (or epinephrine), the two substances first recognized as neurotransmitters.

Since that time many other substances have been identified as transmitters. Furthermore, because of the work of Bernard Katz in the 1950s on quantal release (see Chapter 12), it is usually taken for granted that substances acting as transmitters are stored in vesicles at synapses and released by exocytosis. Nevertheless some substances considered to be neurotransmitters are released into the synaptic cleft directly from the cytoplasm as well as by exocytosis. Thus ideas about neurotransmitters have had to be modified continually to accommodate new information about the cell biology of neurons and the pharmacology of receptors.

As a first approximation, a neurotransmitter can be defined as a substance that is ...