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CLASSICAL PERSPECTIVES |
1 Neurobiology and Cognitive Sectors, SISSA, Via Beirut 2, Trieste, Italy 34014
Email: Nicholls{at}sissa.it
At about the same time as Hodgkin and Huxley's work on squid axons appeared in The Journal of Physiology, Paul Fatt and Bernard Katz published ‘An analysis of the end-plate potential recorded with an intracellular electrode’ (Fatt & Katz, 1951). This was a revolutionary paper that for the first time explained how a chemical transmitter reacted with its receptors to give rise to an electrical signal. Fatt and Katz provided definitive answers to a host of questions regarding acetylcholine-induced permeability changes (questions that experts in the field had not even thought of). Thereafter, it became possible to study transmitters other than acetylcholine, and to analyse transmission in the central nervous system.
What was known about the end-plate potential at that time? Here are some quotes from Fulton's widely read ‘Textbook of Physiology’ (1949):
‘How the nerve impulse produces the end-plate potential has not been settled ...’‘The electrical theory holds that currents from ... nerve terminals are adequate to set up the end-plate potential ...’
‘The chemical theory holds that the transmitter is acetylcholine ...’
‘Nachmansohn ... proposes that acetylcholine is liberated in the (muscle) end-plate by ... current from the nerve ending.’ (Italics in original.)
It would have been an unfair exam question, when I took the BSc Special in Physiology in 1951 (before starting my PhD with Katz), to ask: ‘Explain how activated acetylcholine receptors produce a depolarization at the end-plate’. The discoveries in Fatt & Katz's 1951 paper are so abundant and original that it is hard to do them justice. Here I summarize the principal results. First, intracellular recordings showed that acetylcholine sets up a localized graded potential at the frog muscle motor end-plate; this declines and becomes slowed over distance, in quantitatively the same manner as ‘electrotonic’ potentials produced by injecting current. Second, from values that had been derived for membrane resistance and capacitance, Fatt and Katz estimated the current produced at the end-plate by transmitter. This current was briefer than the voltage change, the time course of which depended on the time constant of the membrane. Moreover, the amplitude of the synaptic current was far too great (approximately 10–12 mol of univalent ions per impulse), to be explained by current spread from tiny nerve terminals or from entry into the end-plate of acetylcholine released by the nerve (a possibility suggested by Fatt in, 1950). Observations that might have appeared trivial explained the mechanism of acetylcholine action: the action potential recorded at the end-plate had a smaller overshoot when it arose from the action of acetylcholine than after direct electrical stimulation of the muscle. This suggested that acetylcholine punched a hole, a leak resistance of about 20 000 
, in the end-plate membrane. This leak allowed ions to flow passively along their electrochemical gradients into or out of the muscle fibre. The receptor mechanism was not sensitive to depolarization. At that time it was not possible to do voltage clamp experiments on muscle: accordingly (so ingenious this!) to test the effect of membrane potential on synaptic currents, the muscle was stimulated electrically to produce an action potential. This swept from one end of the muscle fibre to the other past the end-plate. At the same time the nerve was stimulated to release transmitter at different phases of the action potential. At the peak of the action potential, acetylcholine gave rise to an outward instead of an inward current; at a potential of about –15 mV (during the falling phase), acetylcholine produced no additional current.
Some words about techniques. Today, these experiments would pose few technical problems. But the cathode followers and DC amplifiers available at the time depended on large car batteries and needed constant balancing, the oscilloscope camera was a horror, microelectrodes were pulled by hand the night before, and analysis had to be done by measurements made from projected film. And it is still hard to record reliably from contracting muscles.
The principal conclusions were, first, that the transmitter acts on receptors located at the motor end-plate to open voltage-insensitive channels (not a word that could be used at that time); the increased permeability allowed both sodium and potassium to flow. (In these experiments they could not rule out participation by anions.) As a result, there occurred enormous amplification at the synapse. The voltage change depended on the membrane potential and on the resistance (i.e. diameter) of the muscle fibre.
These experiments created foundations upon which one could formulate new, testable concepts about excitation and inhibition in the central nervous system. Depending on the ion species to which the transmitter made the postsynaptic membrane more permeable, the synaptic signal could drive the potential toward or away from threshold. Indeed, Fatt with Coombs and Eccles (Coombs et al. 1955) later demonstrated anion permeability changes induced by inhibitory transmitters (of unknown identity) in the spinal cord, and by the time their 1951 paper appeared, Fatt and Katz (1951) had already made key observations that led to the discovery of quantal release.
The harmonious partnership of these two marvellous scientists showed how skilful and imaginative experiments can produce completely new approaches to important problems, provided that speculations are constrained by rigorous quantitative measurements. After the appearance of this paper, the study of synaptic transmission became transformed. It is hard for me to define what constitutes ‘beauty’ in science. If I had to point to just one paper to show what I mean, it would be Fatt & Katz (1951).
Original classic paper
The original classic paper reviewed in this article and published in The Journal of Physiology can be accessed online at:
DOI: 10.1113/jphysiol.2006.122143
http://jp.physoc.org/cgi/content/full/jphysiol.2006.122143/DC1
Footnotes
This brief note is dedicated to Paul Fatt with admiration, affection and gratitude for his friendship over many years.
References
Coombs J, Eccles JC & Fatt P (1955). The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential. J Physiol 130, 326–374.
Fatt P (1950). The electromotive action of acetylcholine at the motor end-plate. J Physiol 111, 408–422.
Fatt P & Katz B (1951). An analysis of the end-plate potential recorded with an intracellular electrode. J Physiol 115, 320–370.
Fatt P & Katz B (1952). Spontaneous subthreshold activity at motor nerve endings. J Physiol 117, 109–128.
Fulton JF (1949). Textbook of Physiology, p132. W. B. Saunders, Philadelphia.
This article has been cited by other articles:
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  R. P. Rubin A Brief History of Great Discoveries in Pharmacology: In Celebration of the Centennial Anniversary of the Founding of the American Society of Pharmacology and Experimental Therapeutics Pharmacol. Rev., December 1, 2007; 59(4): 289 - 359. [Full Text] [PDF]
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 G. J. Augustine and H. Kasai Bernard Katz, quantal transmitter release and the foundations of presynaptic physiology J. Physiol., February 1, 2007; 578(3): 623 - 625. [Full Text] [PDF]
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