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Determining the full size of the action potential

Andrew Fielding Huxley

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Introduction

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Any message that passes along a nerve fiber consists of a series of short-lasting electrical events known as action potentials. Each action potential is an explosive change in the membrane potential, i.e. the electrical potential difference between the interior of the fiber and the external fluid. By 1939, it was established that when the nerve fiber is at rest the membrane potential is about 50-100 mV (negative inside), and it was generally believed that this dropped nearly to zero during the action potential. These estimates were, however, very uncertain because they were based on recordings of the external potential. Squids have a pair of exceptionally large nerve fibers (about half a millimeter in diameter), and many experiments that would be impracticable on ordinary-sized fibers can be done on these giant fibers. In the summer of 1939, A. L. Hodgkin and I put an electrode inside fibers of this kind to measure the potential difference directly across the surface membrane, both at rest and when an impulse passed along the fiber. Our result had far-reaching implications for understanding the mechanism of nervous activity.

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Background

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By the latter part of the nineteenth century, it had been established that each nerve fiber is a concentric cable: the cytoplasm is an electrical conductor because of the ions it contains, and the lipid membrane is the insulating sheath. It was also known that when a nerve fiber is stimulated by an electric current, the action potential is set up at the cathode, where current is drawn outwards through the membrane, raising the internal potential. Because this is in the same direction as the change of the membrane potential during an action potential, Hermann proposed that the action potential propagates itself by "local circuits," i.e. the potential change generated at one point on the fiber spreads along the cable structure of the fiber and acts as a stimulus, activating the next point (2456). Hodgkin provided the first experimental evidence that this effect on the membrane potential would be sufficient to cause propagation (2445; 2446).

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Until 1939, the prevailing theory for the origin both of the negativity of the interior of a resting fiber and of the rise of the internal potential during the action potential was due to Julius Bernstein (2454). It was known that the concentration of potassium ions is many times higher inside a nerve fiber than in the surrounding fluid. Bernstein suggested that the resting membrane was moderately permeable to potassium, but not to other, ions, so that K+ ions were able to diffuse outwards, carrying their positive charge and leaving a slight excess of negative charges inside. An equilibrium would be set up in which the attraction of this internal negativity for the positive charge on the potassium ions just balanced their tendency to diffuse outwards. Bernstein's theory for the action potential was that when the internal potential was sufficiently raised, either by an electric shock or by an approaching action potential, the membrane became permeable to all ions, an event commonly described as a "breakdown" of the membrane. The membrane potential would therefore drop to zero, i.e. the action potential would be equal in absolute size to the resting potential, but opposite in direction.

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Keith Lucas had shown that each response by an individual fiber has an explosive, "all or none," character, i.e. its strength is the same whatever the strength or nature of the stimulus that initiated it (2451; 2452). An analogy often used was a burning train of gunpowder.

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In 1937, K. S. (Kacy) Cole and Howard Curtis in the U.S.A. confirmed one aspect of Bernstein's theory by measuring the change in the electrical properties of the membrane of the giant fiber of the squid during an action potential (2441). At rest, the insulating membrane has a high electrical capacity because it is extremely thin, and the resistance in parallel with this capacity is high because the permeability of the membrane to ions is low. They found that the capacity of the membrane did not change during an action potential, so there was no actual "breakdown," but the resistance in parallel with it dropped to a low value. This implied a great increase in the permeability of the membrane to ions, as expected from Bernstein's theory.

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Early in 1939, Hodgkin made external recordings from single nerve fibers from crabs and lobsters. His experiments appeared to show that the action potential was larger than the resting potential, a result not expected from Bernstein's theory. However, deducing the full membrane potential from such external recordings was necessarily uncertain and the results were not published until the end of World War II (2458).

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The experiment

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Figure 1  
Method used by Hodgkin and Huxley (1939) for recording electrical potential inside giant nerve fiber of squid. The photograph is from (2443); 1 scale division = 33 µm. The clear area around the electrode is the giant fiber; the dark areas to right and left of it are masses of small nerve fibers.

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In the late 1930s, Hodgkin and I were both living in Trinity College, Cambridge, he as a Research Fellow, and I as an undergraduate. In early August 1939, I joined him in his research on the giant nerve fiber of the squid at the laboratory of the Marine Biological Association at Plymouth. At his suggestion, I inserted a cannula (a specially shaped glass tube) into one of these fibers so that the fiber hung vertically, and dropped mercury down with the intention of measuring the viscosity of the contents of the fiber. The experiment was abortive: the drops of mercury stopped as soon as they entered the fiber, showing that its interior was a gel, and not a viscous liquid as we had supposed. Hodgkin then saw that we could push a recording electrode down through the cannula and into the interior of the fiber to measure the potential difference across the membrane directly, as illustrated in Figure 1

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Figure 2  
Action potential of giant nerve fiber of squid recorded from inside the fiber. Zero on vertical scale is potential of sea water outside the fiber. (Reproduced from 2443.)

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The electrode was a saline-filled glass tube about 0.1 mm in diameter containing a chlorided silver wire to make a nonpolarizable electrode. We recorded the potential difference with a direct-coupled amplifier, so that the resting potential could be recorded as well as the change that takes place when an action potential passes along the fiber. We found that in the resting state, the internal potential was 40-50 mV negative to the external solution, as was to be expected from external recordings. When we stimulated the fiber, however, the internal potential did not merely rise to equality with the external, as was to be expected from Bernstein's theory, but it went some 40 mV positive (the "overshoot," shown in Figure 2. We just had time to repeat our experiment a few times before we had to leave because war was obviously imminent, and devastating air attacks on British cities were expected. We left Plymouth on 30 August and Hitler's army marched into Poland on 1 September.

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The same experiment was also performed in the summer of 1939 by Curtis and Cole (2442). They, too, found a very large action potential, but they did not recognize the overshoot because they used a capacity-coupled amplifier and therefore could not measure the resting potential.

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The Legacy

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We published our result in a letter to Nature less than one page long (2443). In that letter, we described the method and the result but provided no discussion and no explanation for the overshoot. Hodgkin and I met several times during the war and in 1945, we published a full paper giving four possible explanations for the overshoot, all wrong (2458). It was also in 1945 that we began to discuss the idea that turned out to be correct.

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The concentration of sodium ions inside nearly all cells, including nerve, is only a small fraction of that in the surrounding body fluids. Before the war, it was assumed that this was because cell membranes are completely impermeable to sodium. The fact that sodium can enter and leave cells came to my notice in August 1945, when I attended a lecture by August Krogh, a Danish physiologist famous chiefly for studies of the capillary circulation. He spoke of experiments with radioactive tracers that had been done in Scandinavia during the war, which had shown that sodium ions do enter and leave cells. Metabolic energy would be needed to drive the ions out, since both their concentration difference and the electric potential difference are in the direction to move them inwards. It occurred to me that perhaps the action potential was generated by a temporary cessation of this outward pumping action. When I mentioned this to Hodgkin, he pointed out that if the entry of sodium were fast enough to account for the rising phase of the action potential, the energy required in the resting state to move sodium outwards at an equal rate would far exceed what could be provided by the known consumption of oxygen by nerve. I therefore changed my ground and suggested that the rise of the internal potential during the action potential was due to a short-lived increase in the permeability of the membrane to sodium ions. This increased permeability would be the cause of the drop in membrane resistance found by Cole and Curtis in 1939 (2441).

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At the time, however, there were difficulties in accepting what came to be known as the sodium hypothesis. I was sufficiently naive not to be much worried by these difficulties, but Hodgkin realized that they were very serious. First, the hydrated potassium ion is smaller than the hydrated sodium ion, making it difficult to suppose that a membrane could become more permeable to sodium than to potassium. Second, Curtis and Cole had repeated the internal-recording experiment in the summer of 1940 using a direct-coupled amplifier and had reported two observations, each of which firmly contradicted the sodium idea (2439). They reported overshoots of more than 100 mV, while the greatest value that could be expected from the known sodium concentrations inside and outside the fiber was about 60 mV; Cole later admitted that the very large action potentials were artifacts. Further, they reported that the surrounding solution could be replaced by a sodium-free solution of dextrose without much change in the magnitude of either the resting potential or the action potential. Later experiments, however, have consistently shown that conduction fails in this situation.

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The next step was obviously to test the hypothesis that the internal positivity at the peak of the action potential was due to inward diffusion of sodium ions. This would be done best by internal recording from the squid fiber. The only place in Britain where squid were available, however, was the laboratory at Plymouth, and this had been severely damaged by bombing during the war. Experiments on the squid fiber were therefore not possible until the summer of 1947, when Hodgkin and Bernard Katz made the relevant measurements (2449). They found that the magnitude of the overshoot varied with external sodium concentration Ce, as expected from the Nernst equation for a diffusion potential: V = (RT/F) ln (Ce/Ci) [= 58 log10 (Ce/Ci) mV], where Ci is the internal concentration of sodium ions.

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Figure 3  
Equivalent circuit of unit area of nerve membrane. Vertical arrows show direction of current during action potential. Oblique arrows through RNa and RK indicate that they vary with membrane potential and time. At rest, RNa >> R K. RNa decreases rapidly in response to rise of internal potential, RK decreases with a lag. The decrease in RNa is short-lived.

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I did not take part in these experiments because I was married in July of that year and my wife and I spent the summer on our honeymoon and visiting relatives. We did, however, meet Hodgkin at the International Congress of Physiology in Oxford (21-25 July 1947). In his talk, he mentioned the results that he had so far obtained instead of following the abstract that he and I had submitted. The abstract reported experiments that showed indirectly that potassium leaves a nerve fiber when it conducts action potentials, and that the amount lost was enough to restore the resting potential during the falling phase of the action potential. The full account of this experiment is the first place where the sodium hypothesis is mentioned in print (2447, pp. 364-5). Figure 3 shows the electrical characteristics of the surface membrane that result from these permeability changes.

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In retrospect, the sodium idea seems very obvious, and Hodgkin and I felt that we had been stupid not to think of it at once in 1939. I am sure that we would have done so if either of us had known the paper by Overton, which has a title that translates as " On the indispensability of sodium (or lithium) ions for the contraction of muscle" (2457). Overton describes how he put a frog sartorius muscle into an isotonic sucrose solution when he was investigating osmotic swelling of cells, and found to his astonishment that the muscle became inexcitable. He showed that excitability was restored when a salt of sodium or lithium (but no other cation) was added to the solution, while the anion made no difference. Katz also did not know of this paper, despite having been a student in Germany, but during the war he independently thought of the sodium hypothesis as an explanation of the result that Hodgkin and I had published in 1939.

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Soon after the work of Hodgkin and Katz, we showed that sodium entry is also responsible for generating the action potential in skeletal muscle fibers of frogs (2440) and in myelinated nerve fibers of frogs (2450). However, in crustacean muscle the action potential is generated by calcium entry (2444) and in vertebrate heart muscle both ions are involved (2453). Stämpfli and I also showed, in myelinated nerve fibers, that lithium can substitute for sodium, as Overton had found in muscle.

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The experiments that I have described showed that the action potential is generated by a specific and rapid increase in the permeability of the nerve (or muscle) membrane to sodium ions in response to a decrease in the absolute value of the membrane potential, and that the subsequent recovery to the resting potential is caused by a slower increase in the permeability to potassium ions. This is illustrated in Figure 3. The ways in which these permeabilities vary as functions of membrane potential and time were worked out later by means of the voltage clamp (2455; 2448). When Hodgkin and I had finished this analysis in 1952, we could not see how to make further progress on the mechanism of excitation and conduction, so we moved to other lines of work. We realized that the ion movements took place through specialized sites, or gates, in the membrane, which opened or closed in response to the movement of electric charge under the influence of changes in the membrane potential. These gates have, of course, been identified as protein molecules, but the discovery and characterization of these "channel proteins" have depended on advances in other fields, notably improvements inelectronics and the development of molecular genetics, that were unimaginable in 1952.

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The researchers

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Sir Alan (Lloyd) Hodgkin, O.M., Sc.D., F.R.S. (1914-98) (left in photograph) was born into a Quaker family. His main boyhood interests were in natural history and he entered Trinity College, Cambridge, England, in October 1932 aiming to specialize in zoology. In his first two years he studied zoology, chemistry, and physiology but he chose physiology for his final year's specialization. He then began research on the mechanism of conduction in nerve fibers, and in his first year he gave the first experimental evidence for the local-circuit theory of conduction. He spent the year 1937-38 in the U.S.A. and met K. S. Cole, who introduced him to the giant nerve fiber of the squid, which became his main experimental material. In the summer of 1939, Huxley joined him and they recorded the membrane potential of the squid fiber directly with an electrode inside the fiber, finding that the inside became substantially positive at the peak of the action potential. Apart from work on the development of shortwave airborne radar during World War II, he spent the whole of his working life in Cambridge, holding teaching posts in Trinity College and in the University, and finally as a research professor. After further epoch-making work on the mechanism of conduction, he turned to other aspects of nerve physiology such as the active transport of ions, and finally to the electrical responses of the rods and cones of the vertebrate retina to light. He was President of the Royal Society (1970-75) and Master of Trinity College (1978-84). He shared the Nobel Prize for Physiology or Medicine in 1963 with Huxley and Sir John Eccles.

Sir Andrew (Fielding) Huxley, O.M., Sc.D. (hon.), F.R.S. (1917-) (right in photograph) is a grandson of T.H. Huxley, comparative anatomist and supporter of Darwin, and a half-brother of Julian and Aldous Huxley. His boyhood interests were mostly mechanical but included microscopy. He entered Trinity College, Cambridge, in October 1935, expecting to specialize in physics and to become an engineer. In addition to physics, chemistry, and some mathematics, he took physiology in his first two years and decided to specialize in it. After a year on anatomy as a medical student, he took the final-year course in physiology in 1938-39. He met Hodgkin socially in their college, and received some teaching from him. He started research with Hodgkin, taking part in his recording of the full membrane potential in the giant nerve fiber of the squid just before the war. He joined Hodgkin again in Cambridge after war work in operational research and, with Katz, they followed up that observation, establishing much of what is now accepted about nerve conduction. In 1952 he developed an interference microscope for research on isolated muscle fibers and contributed to establishing the sliding-filament theory. He showed that activation is conducted inwards along the transverse tubules, and he studied the transient responses to sudden length change. In 1960, he moved to University College London, finally returning to Cambridge as Master of Trinity College (1984-90). He was President of the Royal Society (1980-85), and shared the Nobel Prize for Physiology or Medicine in 1963 with Hodgkin and Sir John Eccles.


Prof. A.F. Huxley
Trinity College
Cambridge CB2 1TQ
United Kingdom

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reviews
  • 2439 Curtis, H.J., and Cole, K.S. (1942).  Membrane resting and action potentials from the squid giant axon.  J. Cell. Comp. Physiol. 19, 135-144.  Journal
  • 2440 Nastuk, W.L. and Hodgkin, A.L. (1950).  The electrical activity of single muscle fibers.  J. Cell. Comp. Physiol. 35, 39-73.
  • 2441 Cole, K.S. and Curtis, H.J. (1939).  Electric impedance of the squid giant axon during activity.  J. Gen. Physiol. 22, 649-670.
  • 2442 Curtis, H.J. and Cole, K.S. (1940).  Membrane action potentials from the squid giant axon.  J. Cell. Comp. Physiol. 15, 147-157.
  • 2443 Hodgkin, A.L. and Huxley, A.F. (1939).  Action potentials recorded from inside a nerve fibre.  Nature 144, 710-711.
  • 2444 Fatt, P. and Ginsborg, R.L. (1958).  The ionic requirements for the production of action potentials in crustacean muscle fibres.  J. Physiol. 142, 516-543.  PubMed  
  • 2445 Hodgkin, A.L. (1937).  Evidence for electrical transmission in nerve.  J. Physiol. 90, 183-232.
  • 2446 Hodgkin, A.L. (1939).  The relation between conduction velocity and the electrical resistance outside a nerve fibre.  J. Physiol. 94, 560-570.
  • 2447 Hodgkin, A.L. and Huxley, A.F. (1947).  Potassium leakage from an active nerve fibre.  J. Physiol. 106, 341-367.
  • 2448 Hodgkin, A. L., and Huxley, A. F. (1952).  A quantitative description of membrane current and its application to conduction and excitation in nerve.  J. Physiol. 117, 500-544.  PubMed  
  • 2449 Hodgkin, A.L. and Katz, B. (1949).  The effect of sodium ions on the electrical activity of the giant axon of the squid.  J. Physiol. 108, 37-77.
  • 2450 Huxley, A.F. and Stampfli, R. (1951).  Effect of potassium and sodium on resting and action potentials of single myelinated nerve fibres.  J. Physiol. 112, 496-508.
  • 2451 Lucas, K. (1905).  On the gradation of activity in a skeletal muscle-fibre.  J. Physiol. 33, 125-137.
  • 2452 Lucas, K. (1909).  The "all or none" contraction of the amphibian skeletal muscle fibre.  J. Physiol. 38, 113-133.
  • 2453 Reuter, H. (1967).  The dependence of slow inward current in Purkinje fibres on the extracellular calcium concentration.  J. Physiol. 192, 479-492.  PubMed  
  • 2454 Bernstein, J. (1902).  Untersuchungen zur Thermodynamik der bioelektrischen StrÖme I.  Pflügers Arch. Ges. Physiol. 92, 521-562.
  • 2455 Cole, K.S. (1949).  Dynamic electrical characteristics of the squid axon membrane.  Arch. Sci. Physiol. 3, 253-258.
  • 2456 Hermann, L. (1872). Grundriss der Physiologie, 4th Edition (Berlin: Hirschwald), pp. 323-.
  • 2457 Overton, E. (1902).  Beitrage zur allgemeinen Muskel- und Nervenphysiologie. I Mettheilung. Über die Unentbehrlichkeit von Natrium- (oder Lithium-)Ionen fÜr den Contractionsact des Muskels.  Pflügers Arch. Ges. Physiol. 92, 346-386.
  • 2458 Hodgkin, A.L. and Huxley, A.F. (1945).  Resting and action potentials in single nerve fibres.  J. Physiol. 104, 176-195.
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