Cotransmission

During the mid-1970s, studies on such invertebrates as the mollusc Aplysia showed that at least four different types of transmitters could be liberated from the same nerve terminal. This was the first evidence that Dale's Law does not always apply. Extensive histochemical studies of the mammalian peripheral and central nervous systems followed, and it was shown that transmitters such as acetylcholine, noradrenaline and dopamine can coexist with such peptides as cholecystokinin, vasoactive intestinal peptide, and gastrin-like peptides.

It is now evident that nerve terminals in the brain may contain different types of storage vesicles that store the peptide co-transmitters. Following their release, these peptides activate specific pre- or postsynaptic receptors, and thereby modulate the responsiveness of the membrane to the action of the traditional neurotransmitters such as acetylcholine or noradrenaline. In the mammalian and human brain, acetylcholine has been found to localize with vasoactive intestinal peptide; dopamine with cholecystokinin-like peptide, and 5-HT with substance P. In addition, there is increasing evidence that some peptides may act as neurotransmitters in their own right in the mammalian brain. These include the enkephalins, thyrotrophin-releasing hormone, angiotensin II, vasopressin, substance P, neurotensin, somatostatin, and corticotropin, among many others. With the advent of specific and sensitive immunocytochemical techniques, several more peptides are being added to this list every year. The similarities and differences between the peptide transmitters/co-transmitters and the ''classical'' transmitters such as acetylcholine are summarized in Table 2.5.

The peptide transmitters form the largest group of neurotransmitters in the mammalian brain, at least 40 different types having been identified so far. The mechanism governing their release differs from those of the non-peptide transmitters. Thus peptides are stored in large dense core vesicles which appear to require more prolonged and widespread diffusion of calcium into the nerve terminal before they can be released. In general, the peptide transmitters form part of the slow transmitter group as they activate metabotropic receptors.

Table 2.5. Similarities and differences between the peptide transmitters/

co-transmitters

1. Both neurotransmitters and peptides show high specificity for their specific receptors.

2. Neurotransmitters produce physiological responses in nano- or micromolar (10~9 to 10 concentrations, whereas peptides are active in picomolar (10712) concentrations.

3. Neurotransmitters bind to their receptors with high affinity but low potency, whereas peptides bind with very high affinity and high potency.

4. Neurotransmitters are synthesized at a moderate rate in the nerve terminal, whereas the rate of synthesis of peptides is probably very low.

5. Neurotransmitters are generally of low molecular weight (200 or below) whereas peptides are of intermediate molecular weight (1000 to 10 000 or occasionally more).

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