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Dale's Principle and Communication between Neurones: Based on a Colloquium of the Neurochemical Group of the Biochemical Society, Held at Oxford University, July 1982

Dale's Principle and Communication between Neurones: Based on a Colloquium of the Neurochemical Group of the Biochemical Society, Held at Oxford University, July 1982

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Dale's Principle and Communication between Neurones: Based on a Colloquium of the Neurochemical Group of the Biochemical Society, Held at Oxford University, July 1982

Longueur:
458 pages
4 heures
Sortie:
Oct 22, 2013
ISBN:
9781483150109
Format:
Livre

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Dale's Principle and Communication Between Neurones is based on a colloquium of the Neurochemical Group of the Biochemical Society, held at Oxford University, July 1982. This book focuses on communication between neurones by means of chemical signals.
The book contains an introductory chapter by V. P. Whittaker and nine further chapters on various aspects of the chemical communication processes between neurones. Topics covered include chemical communication between excitable cells; the neuroendocrine division of the nervous system; evidence for a neurone having the capacity to use two chemicals in the same process; and non-synaptic interneuronal communication. Each article is based on the excellent lectures given by the main authors and the discussion which ensued in the one-day colloquium held in Oxford. The final chapter is a specially invited contribution by Drs. Polak and Varndell, who agreed to produce an article on their new method of localising transmitter-like molecules at the electron-microscopic level.
Sortie:
Oct 22, 2013
ISBN:
9781483150109
Format:
Livre

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Dale's Principle and Communication between Neurones - Elsevier Science

USA

What is Dale’s Principle?

V.P. WHITTAKER,     Abteilung Neurochemie, Max-Planck-Institut für biophysikalische Chemie, Göttingen, FR Germany

Publisher Summary

This chapter describes Dale’s principle and communication between neurons of the biochemical society. This principle is very interesting on account of the origins of the evidence for chemical transmission at the synapse. Stimulation of a sensory pathway can often cause vasodilatation—a motor action which involves a cholinergic vasodilator action. However, evidence has accumulated to show that the nerve fibers mediating this antidromic vasodilatation are branches of the sensory fibers and that the central action of the sensory fibers cannot be mediated by acetylcholine. This principle states that the phenomena of regeneration appear to indicate that the nature of the chemical function, whether cholinergic or adrenergic, is characteristic for each particular neuron, and unchangeable. In conformance with Dale’s principle that the same chemical transmitter is released from all the synaptic terminals of a neuron, pharmacological investigation has indicated that acetylcholine mediates the excitation of Renshaw cells by impulses in the collaterals of motor axons just as it mediates the excitation of muscle fibers at the peripheral terminals of the same axon. The chapter describes that there are three possibilities for the origin of the transmitter released on stimulation: (1) the impulses reaching the terminal synthesize the transmitter and then release it, (2) the impulses release transmitter from a neighboring tissue store, and (3) the impulses release transmitter from a preexisting store in the terminal itself.

THE title of this colloquium of the Neurochemical Group of the Biochemical Society is ‘Dale’s Principle and Communication between Neurones’, so perhaps the best way of introducing it is to remind ourselves what ‘Dale’s Principle’ is and how this term arose.

In 1934 Dale gave the Dixon Memorial Lecture to the Royal Society of Medicine and this is reprinted in their Proceedings (Dale, 1935). This is a very interesting account of the origins of the evidence for chemical transmission at the synapse, as it appeared to Dale in 1934. After mentioning the work of such pioneers as Dixon himself, Elliot, Langley, Loewi and, of course, his own earlier work, Dale turned to a problem which was occupying him very much at that time–the problem of the transmitter in the sensory pathway and the phenomenon of antidromic vasodilatation.

It was known that stimulation of a sensory pathway could often cause vasodilatation–a motor action which from Dale’s other work could be expected to involve a cholinergic vasodilator action. However, evidence had accumulated to show that the nerve fibres mediating this antidromic (or ‘axon-reflex’) vasodilatation (Fig. 1a) were branches of the sensory fibres and that the central action of the sensory fibres could not be mediated by acetylcholine. Dale had begun to doubt his own previous belief that antidromic vasodilatation was cholinergic and he reasoned that anyway this was unlikely, as a neurone should have the same transmitter at all its endings. I quote the key passage:

FIG. 1 Diagrams to illustrate (a) ‘axon-reflex’ or ‘antidromic vasodilatation’; (b) inhibition of a spinal motoneurone via a recurrent collateral and inhibitory interneurone (Renshaw cell); (c) inhibitory (I) and excitatory (E) nerve terminals of a cholinergic (C) cell of Aplysia on ‘I’ and ‘D’ cells respectively.

It is to be noted…that…the phenomena of regeneration appear to indicate that the nature of the chemical function, whether cholinergic or adrenergic, is characteristic for each particular neurone, and unchangeable [this was a reference to the finding that sensory fibres could not replace degenerating motor fibres in transplant experiments]. When we are dealing with two different endings of the same sensory neurone, the one peripheral and concerned with vasodilatation and the other at a central synapse, can we suppose that the discovery and identification of a chemical transmitter of axon-reflex vasodilatation would furnish a hint as to the nature of the transmission process at a central synapse? The possibility has at least some value as a stimulus to further experiments.

Now Dale never defined this notion of the nerve cell as a metabolic unit all of whose terminals used the same transmitter as ‘Dale’s Principle’. This expression was coined by Eccles in his book The Physiology of Nerve Cells in 1957 (Eccles, 1957).

Eccles was concerned with a different problem: the mediation of central inhibition. He studied in particular the activation of Renshaw cells by motor neurone recurrent collaterals and the resultant inhibition of motor neurones (Fig. 1b). Initially Eccles rejected completely the notion of chemical transmission and thought that excitation and inhibition could be explained by electrotonic effects of the presynaptic nerve terminals on the postsynaptic cell. He convinced himself, however, that the electrical theory was inadequate and that transmission was chemical, also that the recurrent collaterals on to Renshaw cells were cholinergic, like the motor nerve terminals of the same neurone. He says (p. 163):

In conformity with the principle first enunciated by Dale (1935) that the same chemical transmitter is released from all the synaptic terminals of a neurone, pharmacological investigation has indicated that acetylcholine mediates the excitation of Renshaw cells by impulses in the collaterals of motor axons just as it mediates the excitation of muscle fibres at the peripheral terminals of the same axon.

Then again (p. 184):

The evidence that [synaptic transmission at the junctions between motor-axon collaterals to Renshaw cells] is mediated by acetylcholine has already been presented. It is the first example of a specifically defined cholinergic synapse mechanism in the central nervous system, and is also of interest as an example of Dale’s Principle, which postulates the identity of chemical transmission from the diverse branches of a neurone.

And again (p. 212):

According to a principle first enunciated by Dale (1935) which may be called Dale’s Principle, any one class of nerve cells operates at all of its synapses by the same chemical transmission mechanism. This principle stems from the metabolic unity of a single cell, which extends to all of its branches.

In a later book, The Physiology of Synapses(Eccles, 1964) Eccles discusses another example of what he had called Dale’s Principle, the ability of a neurone in Aplysia to cause excitation in a ‘D’ cell and inhibition in an ‘I’ cell, discovered by Tauc and Gerschenfeld (1961) and Strumwasser (1962) (Fig. 1c). Transmission at either synapse could be blocked by 10−4 d-tubocurarine and atropine and was cholinergic. Eccles thought this was a particularly striking example of Dale’s Principle as indeed it is.

Nowadays, evidence is accumulating that pharmacologically active neuropeptides can coexist with (conventional) neurotransmitters (noradrenaline, 5-hydroxytryptamine and even acetylcholine) in the same neurone. This idea that some neurones might contain more than one transmitter goes back to the work of Burn and Rand (1955) who pointed out that acetylcholine could sometimes exert effects mimicking sympathetic stimulation. They considered various possible explanations and the one they favoured was one in which acetylcholine and noradrenaline was packaged in the same terminal: the effect of stimulation was to release acetylcholine and this by acting on presynaptic receptors on the same terminal released noradrenaline. This was referred to as the ‘Burn and Rand hypothesis’ and at one time excited lively controversy. So far as I know this controversy is still unresolved.

Dale never envisaged that a neurone might contain two transmitters. If he had been aware of that possibility I suppose he would have thought that all terminals of a neurone would release the same two transmitters. Now we know more about the way transmitters are packaged and transported along axons and have at least some evidence that neuropeptides are stored in large dense-cored vesicles while the small-molecular-mass transmitters are stored in smaller vesicles, we can at least imagine that two branches of an axon might have some selectivity for the one package or the other, just as axons have selectivity over dendrites for transmitter vesicles in the first place. So perhaps one could imagine that the ratio, at any rate, in which the two transmitters are released at different endings of the same neurone could vary. To this extent Dale’s Principle might be violated by a neurone using two transmitters.

We deploy many more powerful techniques than Dale had in 1935. Among them are:

– Autoradiography and immunohistochemical methods at the light and electron microscope level.

– Subcellular fractionation techniques whereby terminals and storage vesicles can be isolated and studied in vitro.

– Delicate assay procedures for a variety of transmitters and neuropeptides.

– An understanding of the genetic apparatus and its repression.

– Tissue culture techniques in which derepression of cultured cells may take place, so that they express more than one transmitter type.

No doubt we shall be hearing a lot about these newer techniques in this colloquium and some of the results obtained with them.

No one who has read Dale’s papers (many of which, but unfortunately not the Dixon Memorial Lecture, are collected under the title Adventures in Physiology; Dale, 1953) can fail to be impressed by his insight, by which he was able to speculate on a number of alternative hypotheses and then favour the one which, by and large, later work confirmed.

Thus in discussing the origin of the transmitter released on stimulation (Dale, 1935) he considered three possibilities:

– The impulses reaching the terminal synthesize the transmitter and then release it.

– The impulses release transmitter from a neighbouring ‘tissue store’.

– The impulses release transmitter from a pre-existing store in the terminal itself.

Dale favoured the third alternative and his insight has carried us a long way. Using techniques unavailable to Dale, it has been possible to isolate the transmitter storage organelles from the terminal and to demonstrate directly their extremely high content of transmitter (Whittaker et al., 1964; Whittaker and Sheridan, 1965; Whittaker et al., 1972).

We speculate just as much as our predecessors, but our graphics, may be, are better. Let us hope our insights match theirs in accuracy and depth.

References

BURN, T. H., RAND, M. J. Sympathetic postganglionic mechanism. Nature (Lond.). 1959; 184:163–165.

DALE, H. H. ‘Pharmacology and nerve-endings’ [Walter Ernest Dixon Memorial Lecture for 1934]. Proc. R. Soc. Med., therap. Sect. 1935; 28:319–332.

DALE, H. H. Adventures in Physiology. London: Pergamon Press, 1953.

ECCLES, J. C. The Physiology of Nerve Cells. Baltimore: Johns Hopkins Press, 1957. [and Oxford University Press, London].

ECCLES, J. C. The Physiology of Synapses. Berlinâ€Heidelbergâ€New York: Springer-Verlag, 1964.

STRUMWASSER, F. Post-synaptic inhibition and excitation produced by different branches of a single neurone and the common transmitter involved. Abstr. 22nd int. Congr. Physiol. Sci. 2(no. 801), 1962.

TAUC, L., GERSCHENFELD, H. M. Cholinergic transmission mechanisms for both excitation and inhibition in molluscan central synapses. Nature (Lond.). 1961; 192:366–367.

WHITTAKER, V. P., MICHAELSON, I. A., KIRKLAND, R. J.A. The separation of synaptic vesicles from nerve-ending particles (‘synaptosomes’). Biochem. J. 1964; 90:293–305.

WHITTAKER, V. P., SHERIDAN, M. The morphology and acetylcholine content of isolated cerebral cortical synaptic vesicles. J. Neurochem. 1965; 12:367–372.

WHITTAKER, V. P., ESSMAN, W. B., DOWE, G. H.C. The isolation of pure cholinergic synaptic vesicles from the electric organs of elasmobranch fish of the family Torpedinidae. Biochem. J. 1972; 128:833–845.

Recent Concepts of Chemical Communication between Excitable Cells

G. BURNSTOCK,     Department of Anatomy and Embryology and Centre for Neuroscience, University College London, Gower Street, London WC1E6BT

Publisher Summary

This chapter reviews recent concepts of chemical communication between excitable cells, with particular emphasis on the co-existence of transmitter substances in single nerve terminals. While the classical view is that the autonomic nervous system (ANS) consists largely of antagonistic cholinergic and adrenergic nerves, about fourteen putative neurotransmitters in the ANS have been proposed in the past few years, including various monoamines, polypeptides, purines, and amino acids. Modulatory transmitter mechanisms have also been recognized, including prejunctional inhibition or enhancement of transmitter release, postjunctional modulation of transmitter action, and the secondary involvement of locally synthesized hormones and prostaglandins. The co-transmitters always have synergistic actions on postjunctional effector cells, but two different mechanisms are postulated. (1) If both substances are stored in the same vesicles, release is closely parallel at all impulse frequencies. Upon release, the co-transmitter, in addition to having a direct action on postjunctional cells, may facilitate the action of the other transmitter and act as an inhibitor of its release. (2) If the two substances are stored in separate and different vesicle types, differential release is possible at different impulse frequencies. The peptides released at higher frequencies modulate the role of the classical transmitter, by both prejunctional enhancement of its release and postjunctional facilitation of its action.

Contents

Structural Relationships of Excitable Cells

The Proliferation of Putative Neurotransmitters

Co-existence of Transmitters and Neuromodulation

Acetylcholine and noradrenaline

Classical transmitters and adenosine-5′-triphosphate

Established transmitters with polypeptides

Functional significance of cotransmission

Local Regulatory Mechanisms

‘Axon Reflexes’

‘Trophic’ Factors

Influence of nerve on muscle development

Influence of muscle and associated tissue on nerve development

Identity of trophic factors

Summary

THIS article reviews some of the remarkable new discoveries of the past decade about communication between excitable cells, with particular emphasis on the co-existence of transmitter substances in single nerve terminals and some suggestions about how such systems might operate physiologically.

Structural Relationships of Excitable Cells

Transmission was initially studied most extensively at the skeletal neuromuscular junction (see Katz, 1966) and at ganglionic synapses (see Stok, 1973). Electron microscopy revealed that both these junctions were elaborate with separation of specialised pre- and postjunctional membranes of about 50 nm or less. Transmitters released from presynaptic sites diffused across the narrow cleft to occupy receptors on postjunctional membranes.

One of the most important observations of more recent years, particularly from studies of the autonomic nervous system (Hillarp, 1946; Bennett and Burnstock, 1968) but also from studies of fibres in the CNS (Beaudet and Descarries, 1978), is that many nerves have extensive terminal varicose regions free of Schwann cell envelopments, where vesicle-filled varicosites (1–2 μm in diameter) releasing transmitter en passage are separated by narrow 0.1–0.3 μm diameter) intervaricose regions (Fig. 1). While prejunctional varicosity membranes sometimes show thickenings, there are rarely postjunctional specialisations and the minimum junctional cleft may vary from as little as 20 nm in some densely-innervated tissues (like vas deferens or iris) to as much as 2000 nm in some large elastic arteries (see Burnstock, 1975a; Burnstock et al., 1980). It is still not known what proportion of varicosities release transmitter during a single nerve pulse, but it seems likely that junctions with such a wide cleft and open geometry are amenable to both pre- and postjunctional modulatory influences from locally-released or circulating substances, as well as being the sites of neurotransmission. Some workers define release from preterminal varicosities as ‘non-synaptic’ (see Vizi, this volume), but my own view is that it is not possible to distinguish the relationship of effector cells with preterminal varicosities from that with the terminal varicosity, so that this distinction is not justified (see also Dismukes,

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