Classical transmitter

Cotransmission is transmission through a single synapse by means of more than one transmitter. For example, to elicit vasoconstriction, postganglionic sympathetic neurones release their classical transmitter noradrenaline (which acts on smooth muscle a-adrenoceptors) as well as ATP (which acts on smooth muscle P2 receptors) and neuropeptide Y (which acts on smooth muscle Yx receptors). 

Evidence suggests that co-transmitters in a terminal have their own autoreceptors and, in some cases, activation of their own presynaptic receptor can influence the release of the co-stored, classical transmitter. For instance, activation of P2Y-autoreceptors by ATP is thought to affect the release of noradrenaline from sympathetic neurons. However, in other cases, feedback modulation of release of classical and their associated co-transmitters seems to have separate control mechanisms. This would suggest that either the two types of transmitter are concentrated in different nerve terminals or that mechanisms for regulating release target different vesicles located in different zones of the terminal (Burnstock 1990). 

The release (calcium-dependent) and receptor actions of peptides resemble those of the classical transmitters, the receptors being seven transmembrane-spanning receptors... 

Figure 12.1 A comparison of the production, release and fate of classical transmitters such as glutamate and the monoamines and a peptide. (Most neurons use both classical and peptide transmitters)...

A major difference between the classical transmitters and peptides is that the production of a peptide is quite different since the synthesis of a peptide is in the form of a huge precursor of about 300 amino acids which is produced in the nucleus of the cell and then transported to the terminal being processed en route (Fig. 12.1). The prepropeptide is produced by translation in ribosomes and so occurs only in cell bodies or dendrites while the classical transmitters are produced at the terminal via a short series of enzymatic steps from a simple precursor. The study of the production of the propeptides have revealed a series of principles in that ... 

The peptides will now be considered individually in some detail. It must be noted that the large molecular size of the peptides means that they are even less likely to cross the blood-brain barrier than classical transmitters and the instability of peptides means that full functional studies require non-peptide agonists and antagonists. Whereas nature has provided morphine and medicinal chemists have made naloxone, tools are lacking for many other peptides. 

Figure 12.2 A hypothetical synapse where co-existence of peptides and classical transmitters occurs. A is a classical transmitter whereas B and C are peptides. The slow synthesis of peptides and the need for axonal transport may mean that in active neurons, the classical transmitter may be released under all conditions, but the peptide(s) may require higher intensities of stimulation for release and be depleted if the neuron continues to fire for long periods. Competition for peptidases can lead to changes in levels of two co-released peptides. At the postsynaptic site, the receptor mechanisms of the co-existing transmitters can also produce complex changes in neuronal activity...

Walker, R.J., Brooks, H.L. and Holden-Dye, L. (1996) Evolution and overview of classical transmitter molecules and their receptors. Parasitology 113, S3-S34. 

Histamine in the brain may act as both a neuromodulator and a classical transmitter 261... 

Regulation of neuropeptide expression is exerted at several levels. Control of neuropeptide function is mediated by factors controlling rates of prepropeptide gene transcription, translation, peptide degradation and secretion (Fig. 18-11). On the scale of seconds to minutes, peptide secretion is not always coupled lock-step with classical transmitter release (example above). Peptides are inactivated by diffusion and by proteolysis, so it would be expected that inhibition of specific extracellular proteases... 

The drugs discussed in this section produce a direct relaxation of vascular smooth muscle and thereby their actions result in vasodilation. This effect is called direct because it does not depend on the innervation of vascular smooth muscle and is not mediated by receptors, such as adrenoceptors, cholinoreceptors, or receptors for histamine, that are acted on by classical transmitters and mediators. 

Classical transmitters, their synthesis, degradation and receptors.372... 

Moneypenny, C.G., Kreshchenko, N., Moffett, C.L., Halton, D.W., Day, T.A. and Maule, A.G. (2001) Physiological effects of FMRFamide-related peptides and classical transmitters on dispersed muscle fibres of the turbellarian, Procerodes littoralis. Parasitology 122, 447- 155. 

Ribeiro, P., El-Shehabi, N. and Patockas, N. (2005) Classical transmitters and their receptors in flatworms. Parasitology (in press). 

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