Ionotropic and metabotropic neurotransmission

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do not increase conductance at the postsynaptic membrane.

Ionotropic and metabotropic neurotransmission John C. Eccles and Patrick L. McGeer Communication across synapses in the mammalian nervous system is now acknowledged to be achieved by chemical rather than electrical transmission. Each neurone is believed to manufacture usually one neurotransmitter which is released in a calcium-dependent fashion upon axonal stimulation. This is the biochemical f'mger-print of the neurone, and the specific molecule stored in its synaptic vesicles. Close to a dozen such compounds have been shown to meet reasonable criteria for synaptic transmitters*. These compounds seem to have widely different effects on the postsynaptic neurones, necessitating a broader interpretation of what is meant by neurotransmission. We would suggest that the diversities of postsynaptic actions can be resolved into two distinct classes. An important point is that it is the postsynaptic actions which are discriminated, not the transmitters. For example, acetylcholine can have two distinct actions on the sympathetic ganglion cell: nicotinic and muscarinic and, via the SIF (Small, Intensely Fluorescent sympathetic) cell, a slow inhibitory action as well. Because of the essential features of the postsynaptic actions, they will be named ionotropic and metabotropic, as has been fully described in our current book s .

Ionotropic transmission Ionotropic transmission is in the classic mode. The transmitter acts specifically to open ionic gates in the postsynaptic membrane, its postsynaptic effect being initially due to the passive diffusion of ions through the opened channels. The latency of action is very short - about 1 ms - there being a membrane potential change dependent on the equilibrium potential of the ions passing through the channels. For example, at the neuromuscular junction the endplate potential is dependent on the diffusion 11 of K* and Na ÷, and a similar ionic mechanism is responsible for the

ionotropic transmission in a sympathetic ganglions . Since the equilibrium potential for the excitatory postsynaptic potential in the central nervous system is also about zero, a similar ionic mechanism is assumed=. Acetylcboline at the neuromuscular junction or on Renshaw cells of the spinal cord is the classical excitatory ionotropic neurotransmitter. Glutamate (and aspartare) at higher CNS centres function in a similar fashion. G A B A and glycine are the classical ionotropic inhibitory neurotransmitters and are effective largely by opening chloride gates. The IPSP is hyperpolarizing because of the lower CI concentration inside the nerve cell7, as compared with the extracellular fluid. If the CI- concentration were higher inside the nerve cell, then G A B A would have a depolarizing effect instead. Ionotropic transmitters are the workhorses of the nervous system. Their tasks are relatively simple and it may be that few of them exist. Thus, the characteristic features of ionotropic transmission are: (1) Short latency- about 1 ms. (2) Increased conductance at the postsynaptic cell membrane due to opening of ionic gates. (3) Membrane-potential change dependent on increased ionic conductance and on the equilibrium potentials of the ions diffusing through the opened channels. (4) Duration of potential change only slightly longer than transmitter action.

Metabotropi¢ transmission The remainder of the neurotransmitters, including acetylcholine at muscarinic synapses, seem to operate in a different fashion. This we describe as metabotropic. It must be appreciated that only the barest outlines of what may be involved in metabotropic action are available as yet. The essential requirement is that the *Acetylcholine, GABA, glycine, dopamme, nor- transmitter acts indirectly, by triggering a adrenaline, adrenaline, serotonin, glutamic (aspartic) acid, and substance P; possibly histamine, taurine, chemical reaction, or a series of reactions, enkephalin, neurotensin, somatostatin, and a few other in the postsynaptic cell. Since they do not peptides. affect postsynaptic ionic gates directly, they

Dopamine Dopamine is the best studied metabotropic transmitter. The r e ~ p t o r is linked to adenylate cydase, and stimulation by dopamine leads to the production of cyclic AMP (cAMP) s. cAMP, the second messenger, is located in the postsynaptic cell, and is presumed to phosphorylate a protein, or proteins, which initiate the postsynaptic response. Protein kinases are known to be capable of carrying out a wide spectrum of highly specific biochemical actions, so the potential for a metabotropic system such as this one is obviously very great. The protein kinases could, for example, activate an electrogenic pump to hyperpolarize or depolarize the membrane. They could alter microtubular function, or stimulate RNA and protein synthesis. Unfortunately, what does take place in the postsynaptic cell as a result of activation of receptors by dopamine or any of the metabotropic transmitters is not known precisely. This remains as one of the great challenges for future neuroscience research. Some hints have been given by the studies of Greengard +, LibeP, and their colleagues, on the superior cervical ganglion. Here they have shown that a brief pulse of dopamine into the perfusing fluid will greatly enhance the subsequent excitation brought about by stimulation of preganglionic cholinergic fibres. The changes are not transient, but endure for some hours. Physiologically, such dopamine activation could come from SIF cells located in the ganglion. A somewhat comparable phenomenon has been observed by York and Lentz 1= who stimulated briefly the substantia nigra in rats and found in the caudate a prolonged enhancement of response to peripheral stimulation. The frustrations of trying to classify a metabotropic transmitter as either excitatory or inhibitory are no better illustrated than in the case of dopamine. Many investigations have concluded that the electrophysiological effects of dopamine are inhibitory°; others have found them to be excitatory'; and, in one study in the mollusc, either excitatory or inhibitory effects were obtained from the same neurone depending on the position of the iontophoresis micropipette 1. It is not necessary to hypothesize any ionotropic action of dopamine to explain the fact that it influences profoundly extrapyramidal, EIscvier/Norlh-Holland Biomedical Pr¢ss 1979

40 behavioural, and neuroendocrine activities. These correlate well with the major dopamine pathways, namely the nigrostriatal, mesolimbic, and tuberoinfundibular tracts, respectively. A metabotropic influence, whereby postsynaptic cells are sensitized by dopamine to give a modified response to subsequent, more discrete ionotropic input would adequately account for the results.

Noradrenaline Noradrenaline is a metabotropic transmitter whose receptor is evidently also linked to adenylate cyclase. While the second messenger, cAMP, is the same for dopamine and noradrenaline, the receptors are different. There seems to be little cross-reactivity between the two. Again it is not known precisely what cAMP does in neurones postsynaptic to noradrenaline nerve endings, although many suggestive experiments have been carried out. Acetylcholine The receptor for acetylcholine at muscarinic sites is thought to be linked to guanylcyclase, with cyclic GMP (cGMP) being the second messengera. Serotonin Serotonin (5-HT) has many of the properties expected of a metabotropic neurotransmitter, although very few statements can be made about its receptor system. Serotonin seems to produce relaxation and sleep, and therefore might be anticipated as having contrasting postsynaptic effects to the catecholamines. In common with the catecholamines, it apparently has no ionotropic actions. Also in common with the catecholamines, its anatomical distribution is unsuited to discrete action. The raphe system, which contains virtually all of the 5-HT cell bodies, is extremely small. Yet the nerve endings ramify to innervate almost all areas of brain. A metabotropic action, whereby serotonin would modify the responses of more discrete ionotropic input to postsynaptic cells would be compatible with its observed anatomical and physiological effects.

Peptides The peptides are only now coming under intensive study as substances confined to specific neuronal pathways in the manner of other neurotransmitters. Some appear to exist only in the hypothalamic-pituitary axis. But others, such as substance P, neurotensin, the enkephalins,/3-endorphin, somatostatin, and thyrotropinElsevier/North-Holland Biom~licai Press 1979

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releasing hormone, all have wider distribution in brain. They have many effects. Neurotensin, as one example, has been shown in the periphery to affect glucoregulatory, haemodynamic, smooth muscle, neuroendocrine, thermoregulatory, and gastric secretory systems. While its effects on brain cells are not yet known, the metabotropic possibilities are many, just as they are for the other peptides. There must, of course, be other methods of signalling in the nervous system besides the conventional release of vesicle-bound neurotransmitters. This might involve the release of long-acting substances of metabotropic character from nerve endings or dendrites in addition to the transmitter. There is, first of all, the immense problem of the building of the brain and the establishment of lines of communication. This in itself must involve the most subtle kinds of signals between neurones. But the brain once built is not a fixed unchanging machine. Modifiability is the essence of its performance. Here, plasticity of nerve endings is probably involved. Only in recent years have we come to recognize the degree to which synaptic connections lead a life of ebb-and-flow. Damaged nerve endings are replaced by sprouts which may be either homotypic, or, if homotypic lines are not available, heterotypic8.1°. Since a neurone, deprived of its axon, or even its transynaptic input, can degenerate, there must be chemical signalling which is critical to the

maintenance of the neurone itself. This too must be a long-term metabotropic effect. We are still in the most primitive stages of understanding what is involved in the way of chemical communication between neurones in the CNS. By recognizing the concept of metabotropism we will at least have taken the first step towards investigating what may be involved

Reading list 1. Ascher,P. (1973) In: E. Usdin and S. H. Snyder (eds), Frontiers in Catecholamine Research, Pergamon Press, N.Y., pp. 667-672. 2. Eccles, J. C. (1964) Physiology of Synapses, Springer-Verlag. 3. Greengard, P. (1976) Nature (London) 160, 101-108. 4. K~itai,S. J., Wagner,A., Precht, W. and Ohne, T. (1975) Brain Res. 85, 44-48. 5. Koketsu, K. (1969) Fed. Proc. 28, 101. 6. Libet, B., Kobayashi,H. and Tanaka, T. (1975) Nature (London) 258, 155-157. 7. Luse, H. D. (1971) Science 173,555-557. 8. McGeer, P. L., Eccles,J. C. and McGeer,E. G. (1978) Molecular Neurobiology of the Mamrnalian Brain, Plenum Press, N.Y. 9. MeLennan, H. and York,D.H. ¢1967) Z Physiol. 189, 393-402. 10. Raisman,G. (1969) Brain Res. 50, 241-264. 11. Takenchi,A. and Takenchi, N. ( 1960)J. Physiol. 154, 52-67. 12. York, D. H. and Lentz, S. (1976) Neuroscience Abst.,

no. 100.

SirJohn Ecclesand P. L. McGeerhave collaborated in work carried out at the Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada, V6T lWS. (Sir John bases his present activities from Contra in Switzerland.)

Schmidt-Lanterman incisures and Wallerian degeneration G. AIIt In this article, Gerry Allt describes the structures o f the myelin sheath (first identified by Schmidt and Lanterman) in which the Schwann cell cytoplasm is to be found. He then continues, to describe the alterations in the myelin lamellae adjacent to these 'incisures' following a proximal crush o f the nerve.

In myelinated peripheral nerve fibres the myelin sheath is discontinuous at the 'nodes of Ranvier'. This is the corollary of the fact that the myelin sheath is an integral part of the Schwann cell, and adjacent cells are separated by distinct

spaces (nodal gaps). Between the nodes of Ranvier the myelin membranes (lamellae) form continuous layers which are compact, except at the 'incisures' or 'clefts', first described by Schmidt and Lanterman in the last century. In fact, these are