J Physiol 578.
3 (2007) pp 621–622
CLASSICAL PERSPECTIVES
How acetylcholine gives rise to
current at the motor end-plate
John G. Nicholls
Neurobiology and Cognitive Sectors, SISSA,
Via Beirut 2, Trieste, Italy 34014
Email: Nicholls@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
This brief note is dedicated to Paul Fatt with
admiration, affection and gratitude for his
friendship over many years.


C 2007 The Author. Journal compilation

C 2007 The Physiological Society
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 ‘electro-
tonic’ 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 trans-
mitter. 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 acetyl-
choline 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), acetyl-
choline 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
621
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).
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.
DOI: 10.1113/jphysiol.2006.122143
622
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.
Classical Perspectives
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.


C 2007 The Author. Journal compilation

J Physiol 578.3
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
C 2007 The Physiological Society