Cotransmission
Introduction
After some early hints, the possibility that some nerve fibres synthesise, store and release more than one nerve transmitter that produces changes in postjunctional activity via specific postjunctional receptors was postulated by Burnstock in 1976 [1], challenging what had become known as Dale’s Principle — the concept that nerves utilise only one transmitter [2]. Soon after, Hökfelt et al. [3] focused on the colocalisation, vesicular storage and release of peptides from both peripheral and central nerves. Colocalised substances are not necessarily cotransmitters; however, they can (especially peptides) act as pre- and/or postjunctional neuromodulators of the release and actions of the principal cotransmitters. For example, neuropeptide Y (NPY) synthesised, costored and released from sympathetic nerves in several preparations does not have a direct action on postjunctional cells, but rather acts as a pre- and postjunctional modulator of both the release and the actions of noradrenaline (NA) and ATP 4., 5. (Figure 1j).
Several reviews of the early literature on cotransmission are available 6., 7., 8., 9., 10.. Most of the early studies were carried out on vertebrate autonomic and invertebrate nervous systems [6]. ATP and NPY were established as cotransmitters with NA in sympathetic nerves supplying both visceral and cardiovascular systems. Vasoactive intestinal polypeptide (VIP) and ATP were shown to be cotransmitters with acetylcholine (ACh) in parasympathetic nerves. The ‘chemical coding’ of neurotransmitters in the gut were described [11], including non-adrenergic non-cholinergic inhibitory nerves utilizing a combination of ATP, nitric oxide (NO) and VIP. Calcitonin gene-related peptide (CGRP) and substance P (SP) were identified as cotransmitters in sensory-motor nerves (together with ATP in some fibres), as were ACh and ATP in motor nerve endings. The proportions of these cotransmitters vary considerably between species and organs, and show plasticity of expression during development and in pathological conditions [6]. In general, classical transmitters are contained in small synaptic vesicles, whereas peptides are stored in large granular (dense-cored) vesicles (LGVs), although small molecule transmitters are sometimes stored together with peptides in LGVs 12., 13.•.
Recent interest has focused on the mechanisms that underlie cotransmission and its physiological significance 13.•, 14., 15.; these issues are discussed in this review.
Section snippets
Central nervous system
Evidence for ATP being a cotransmitter with established neurotransmitters in the nervous system has recently been reviewed [16••]. In preparations of affinity-purified cholinergic nerve terminals from the rat cuneate nucleus, ATP and ACh are co-released. Co-release of ATP with catecholamines from neurons in the hypothalamus and locus ceruleus has been reported, and there is recent evidence for co-release of ATP with γ-amino butyric acid (GABA) in dorsal horn and lateral hypothalamic neurons 17.
Invertebrate cotransmitters
The neuropeptide proctolin is a cotransmitter with SchistoFLRFamide, octopamine and probably glutamate in nerves supplying the oviduct of the locust [31]. GABA and a catecholamine (probably DA) are colocalised in a subpopulation of interneurones within the central pattern generator currents that control feeding-related behaviours in Aplysia [32•]. Neuropeptides are colocalised with classical transmitters in the crayfish stomatogastric nervous system [33]. Various neuropeptides, including
Physiological significance of cotransmission — synaptic integration
Several major themes have emerged about the physiology of cotransmission; these are described below.
Cotransmitter plasticity: control of transmitter expression
Cotransmitter plasticity during development and ageing, following trauma or surgery and after chronic exposure to drugs, as well as in disease, has been reviewed by Burnstock [6]. In a recent study using primary cultures of neonatal rat spinal neurones, evidence was presented for the regulation of SP (NK1) receptor expression by CGRP [49•]. There were some outstanding early studies of the factors influencing cotransmitter expression in sympathetic nerves [50], and a physiological role for
Conclusions
To establish that compounds shown to be localised in nerves are actually cotransmitters, several criteria need to be satisfied:
- 1.
The substance is synthesised and stored in the nerve.
- 2.
The substance is released upon nerve stimulation.
- 3.
Specific receptors for the substance need to be identified on postjunctional sites that, when occupied, lead to changes in postjunctional activity.
- 4.
A transport system needs to be present for the substance itself or its breakdown products, uptake of which leads to renewal
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
- •
of special interest
- ••
of outstanding interest
Acknowledgements
I would like to thank Chrystalla Orphanides for her splendid help in the preparation of this review.
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