R. D. KEYNES 



very much narrower range. The resting potential generally lies between 60 and 90 

 mV, while during activity the potential is reversed by 30 to 60 mV. 



Another feature which all these tissues have in common is their possession of a high 

 internal potassium and low sodium content. The actual concentrations are, of course, 

 higher in marine invertebrates like squid and cuttlefish (the body fluids of which are 

 isotonic with sea water) than in mammals and other vertebrates, but there is a general 

 similarity between the concentration ratios in all species. Thus there is usually about 

 twenty times as much potassium inside the cells as outside, but only one-tenth as much 

 sodium. This has been shown particularly well in the case of giant squid axons, the 

 axoplasm of which can be extruded and analysed without any complications arising 

 from the presence of indeterminate quantities of extracellular material. 



These observations can most satisfactorily be explained on the basis of the ionic 

 hypothesis put forward by Hodgkin, Huxley and Katz, the evidence for which has 

 been reviewed by Hodgkin (1951). It is suggested that the resting nerve membrane is 

 relatively permeable to K+ and CI - ions, and impermeable to Na+ ions. When the 

 membrane is depolarized by 1 5 mV or more, either by application of a cathode, or 

 by local circuit action when a neighbouring portion of the nerve becomes active, its 

 permeability to Na + rises temporarily much above that to any of the other ions 

 present. Sodium ions then begin to move inwards, driven by the concentration 

 gradient, thus depolarizing the membrane further, and increasing the sodium per- 

 meability still more in a regenerative fashion. The inward movement of sodium con- 

 tinues until the peak of the action potential is reached. Here it ceases, both because 

 the mechanism responsible for raising the sodium permeability becomes inactivated, 

 and because the membrane potential has now arrived at a level close to the equi- 

 librium potential for sodium. At this point, the potassium permeability of the 

 membrane is raised to a value considerably greater than its resting one, and a net 

 outward movement of K+ ions takes place, quickly restoring the membrane potential 

 to its original resting level. After a brief refractory period while the sodium and potas- 

 sium permeability systems recover to their normal quiescent state, the nerve is ready 

 to conduct another impulse. It has lost a small amount of potassium in exchange for 

 sodium, and it is from these downhill ionic movements, which must ultimately be 

 reversed by an ionic pump harnessed to metabolism, that energy is derived for the 

 electric currents which flow during propagation of the impulse. 



The major pieces of evidence in support of these ideas are as follows: 



(1) Conduction is blocked in a medium from which sodium is absent. Exceptions 

 to this statement are that lithium, but no other cation, will act as a substitute for 

 sodium, and that in crustacean muscle the mechanism of conduction appears to 

 differ from that just described (Fatt and Katz, 1953). 



(2) The relationship between external sodium concentration and the extent to 

 which the membrane potential is reversed at the peak of the spike conforms closely 

 to that predicted by the hypothesis. Desmedt (1953) has now shown that in frog- 

 muscle the effect of varying the internal sodium concentration also fits well with 

 theoretical expectation. 



(3) Studies with radioactive sodium and potassium have shown that in non- 

 myelinated invertebrate nerves the effect of stimulation is to accelerate the ionic 

 movements in both directions. From these experiments, and from analyses of squid 



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