SKELETAL NEUROMUSCULAR TRANSMISSION 



20 n 



modification of the action potential response by 

 junctional activity. The effect of this activity is con- 

 sistently to cause a deviation toward a level near 

 zero membrane potential. This accounts for the reduc- 

 tion in peak amplitude of the spike and the delay on 

 the falling phase. As a first approximation it may be 

 assumed that the fundamental changes effected in 

 the membrane by the two types of activity which are 

 superimposed at the junction (i.e. spike and junctional 

 activity) do not interact. The effect of transmitter 

 action on the spike, as well as the initial development 

 of the endplate potential, can then be satisfactorily 

 accounted for by an increase in membrane conduct- 

 ance in series with an emf set near the level of zero 

 membrane potential. However during the action 

 potential the situation is complicated by the presence 

 in the membrane of two important components of 

 conductance, one due to the passage of sodium ions 

 and the other to potassium ions, which follow different 

 time courses and are dependent on the level of mem- 

 brane potential. In order to determine the effect of 

 transmitter action more accurately, the spike has been 

 set up independentlv of the nerve response by direct 

 stimulation of the muscle fiber (24). In this way, using 

 a suitably timed nerve impulse, transinitter action was 

 made to begin at any chosen stage of the action po- 

 tential process, and the resultant deviation of the 

 potential observed. It was thus shown that the 

 equilibrium potential for junctional activity lies 

 between 10 and 20 mv, with the interior of the fiber 

 negative. 



The generation of the endplate potential has also 

 been studied in the absence of an action potential by 

 applying a steady current to the muscle fiber and 

 thereby altering the membrane potential at which 

 the transmitter operates. .Significant results have been 

 obtained only with currents directed inwardly across 

 the membrane and causing a hyperpolarization, 

 since with currents in the opposite directions complica- 

 tions arise owing to the initiation of muscle action 

 potentials. The endplate potential was found to vary 

 in such a manner as to maintain its rate of rise nearly 

 directly proportional to the level of membrane po- 

 tential at which it occurred. An equally good fit of 

 the data could be obtained with a straight line for 

 which zero respon.se would occur at a membrane 

 potential of 15 mv, internally negative. There is thus 

 complete agreement, as far as the equilibrium value 

 is concerned, between the results obtained from the 

 effect of junctional activity on the membrane at rest 

 and on the membrane undergoing an action po- 

 tential. 



In the case of the endplate potential arising in the 

 otherwise resting membrane, an analysis has been 

 made to determine what size the added conductance 

 would have to be to produce the observed rising phase 

 of the response. The muscle filler has been treated as 

 a cable with known distributive characteristics, and 

 the conductance has been considered as applied 

 suddenly at a point along this cable. From the change 

 of potential occurring in the uncurarized muscle up 

 to the level at which the spike is initiated, the con- 

 ductance is calculated to correspond to a resistance 

 of about 20,000 ohms. This may be considered in 

 relation to the resting resistance of about 500,000 

 ohms, which is shunted as a result of junctional 

 activity, and which is in effect the resistance of the 

 membrane over a length of about 4 mm of fiber (twice 

 the space constant of the fiijer). An analysis has also 

 been made of the effect of junctional activity to reduce 

 the reversal of membrane potential at the .summit of 

 the spike, together with any additional displacement 

 produced by an applied current. The added conduct- 

 ance calculated from this information is roughly in 

 agreement with the value obtained from the rising 

 phase of the endplate potential. 



There appears thus to be a convergence of evidence 

 to show that the effect of junctional activity on the 

 muscle fiber membrane can be represented as the 

 addition of a conductance in scries with a fixed emf 

 This may further be interpreted as the creation of a 

 new path for the diffusion of ions across the mem- 

 brane. The equilibrium value (15 mv, internally 

 negative) toward which the membrane potential is 

 displaced is the same as the emf that would be 

 expected to occur for the unrestricted diffusion of ions 

 between two solutions, having the ionic composition 

 of the intra- and extracellular media. It is therefore 

 concluded that in the new diffusion path created by 

 transmitter action, no selectivity is exerted in the 

 passage of different ion species other than that already 

 existing in the aqueous media on the two sides of the 

 membrane. 



The investigations on neuromuscidar transmission 

 considered so far in this section have concerned the 

 amphibian muscle fibers that under normal conditions 

 respond to a nerve impulse with a twitch. The con- 

 clusions reached, as to the fundamental alteration in 

 the postjunctional membrane produced by the action 

 of the transmitter, seem likely to be valid generally for 

 junctions on vertebrate skeletal muscle fibers. How- 

 ever, marked variations in the overall electrical 

 response have been found to occur in different prepa- 

 rations, and these are adduced to stem mainly from 



