From Muscle Endplate to Brain Synapses : Review A Short History of Synapses and Agonist-Activated Ion Channels

A. V. Hill was, at the time, an undergraduate of Trinity College Cambridge, though he later held the Chair of Biophysics at University College London, in which job he was succeeded by Bernard Katz. Hill’s ideas were developed over the next 30 years by A. J. Clark (e.g., David Colquhoun* and Bert Sakmann† *Department of Pharmacology University College London Gower Street London WC1E 6BT United Kingdom Clark, 1933) and were extended to competitive antagonists at equilibrium by John Gaddum (e.g., Gaddum, †Max Planck Institut für Medizinische Forschung Jahn-Strasse 29 1937) and Heinz Schild (all three of whom held the Chair of Pharmacology at University College London). 69120 Heidelberg Federal Republic of Germany There was, of course, no hint in 1878 that these observations had anything to do with synaptic transmission. That idea was developed by Henry Dale and his colleagues and was well established by the 1930s, through Introduction classical papers such as Dale, Feldberg, and Vogt This review gives a very personal view of some of the (1936). This done, the way was paved for the study of work that has led up to the present state of knowledge agonist-activated ion channels, which had its roots in about synapses and ion channels. It would take a whole the 1940s and 1950s, although they were not called ion book to do justice to this topic, and we can only apolochannels until later. Since then, we have learned how gise in advance for failing to mention by name most of to measure the current flow through channels, we have the people who have played an important part. Many of learned much about the rates at which agonists bind the “new” ideas that are proclaimed daily are actually and channels open and shut, and we know the primary quite old, and it is perhaps appropriate to remind the structure of many channels and the shape of one of present generation of neuroscientists of how current them (Unwin, 1995). But we still do not know in any detail views have evolved. A surprising number of them can how the function of a receptor relates to its structure,nor be found in the prescient work of Bernard Katz and his how exactly the agonist causes the structural recolleagues at University College London, to whom this arrangement that is involved in opening and shutting. article is a tribute. Katz made fundamental contributions Work on synaptic transmission in the brain, which had to bothpresynaptic (transmitter release) and postsynapbeen pioneered by Eccles and others (see Eccles, 1964), tic (ion channel) aspects of synaptic transmission. We underwent an enormous explosion after the introduction shall concentrate on the latter, and Erwin Neher will of brain slices and the patch clamp. We are now apdiscuss presynaptic events in the next review. proaching the end of the “decade of the brain,” and The idea of a receptor originated in the nineteenth despite a great deal of interesting work and a lot of talk, century, from the work of Paul Ehrlich and J. N. Langley. it cannot honestly be said that there has been any great Langley studied the actions of atropine and pilocarpine, conceptual advance on the major issues; at the end of and in 1878 he noted (in the first volume of the Journal the decade, we not only still do not understand memory, of Physiology, which he founded) that the inhibitory acbut we still do not understand even long term potentiation of atropine could be overcome by increasing the tion. Perhaps it should have been a “century of the dose of pilocarpine. Moreover, the restored response brain. ” What has been achieved is a considerable into pilocarpine could in turn be abolished by further atrocrease in the understanding of individual synapses in pine. Commenting on these results, Langley wrote: the brain. In some ways, they have turned out to be “We may, I think, without too much rashness, assume quite similar to the neuromuscular junction—very brief that there is some substance or substances in the pulses of transmitter open postsynaptic ion channels, nerve endings or [salivary] gland cells with which both which depolarise or hyperpolarise the postsynaptic cell, atropine and pilocarpine are capable of forming comand the time course of events is controlled largely by pounds. On this assumption, then, the atropine or the rates of binding and opening of the receptor channel pilocarpine compounds are formed according to molecule itself. In other ways, though, central synapses some law of which their relative mass and chemical are vastly more complicated. affinity for the substance are factors. ”