86 PHYSIOLOGICAL TRIGGERS 



small spontaneous potentials of rather uniform size and shape occur. Each 

 rises rapidly (1-2 msec.) to a maximum amplitude of 0.5-1.0 millivolts, and 

 then slowly decays over the course of 20-30 milliseconds. The existence of 

 a minimal amplitude response and a stepwise (rather than a continuous) in- 

 crease in amplitude suggests some basic functional unit. Extensive, careful 

 work by these investigators has led to the tentative hypothesis that the unit 

 responsible for such a potential is a single active 'carrier' molecule for ACh, 

 each carrier molecule making possible the passage of perhaps several thousand 

 ACh molecules through the nerve ending in the course of a few milliseconds. In 

 this picture the occasional freeing of a carrier molecule from an inactive state 

 gives rise to these randomly occurring, miniature potentials. When, under the 

 effects of a nerve impulse, many of these carrier units are brought simultane- 

 ously into action, sufficient ACh can be released at one time to produce a critical 

 depolarization and to bring about a propagated impulse in the muscle fiber. In- 

 direct evidence indicates that the amount of ACh released through the action 

 of a nerve impulse increases with calcium concentration over a range of low 

 concentrations. It is speculated that at least some of the carrier molecules in 

 their normally inactive state are combined with calcium, and that a nerve im- 

 pulse acts only on this complex to create the active carrier molecule (20). 

 Thus, an increase in calcium concentration could be reflected in an increase in 

 the Ca-carrier concentration and a more effective response to a nerve impulse. 

 Whether the hypothetical carrier molecule actually performs some sort of 

 rapid shuttle service (being associated momentarily with each ACh molecule 

 released), or whether it acts as a true trigger in simply unlocking the flood-gate 

 for an outpouring of ACh, is not known. But, in any case, the amount of ACh 

 released by a single unit appears to be very nearly constant. The first possibility 

 cannot be dismissed simply on the basis that the required turnover rate would 

 be too high. For example, even with lowered estimates for the molecular weight 

 of cholinesterase, the enzymatic turnover rate for ACh (and hence the rate of 

 complex formation between ACh and the enzyme) might well be of the order 

 required here. Possibily some other molecule (carrier) is equally adept at com- 

 bining with ACh rapidly and also fleetingly. A single carrier molecule with 

 many binding sites for ACh could also be hypothesized in order to relieve the 

 demands made on a single site without losing the unitary character of the 

 response. 



Several years ago it was found that the end-plate regions of a muscle fiber are 

 much more sensitive to ACh than are the non-end-plate portions (12, 60). 

 Recent work has shown that the ACh-sensitive 'receptors' must be localized in 

 the outer surface of the muscle membrane in the end-plate region, since ACh 

 supplied intracellularly to this region fails to cause a response (22). The nature 

 of the receptor is not known. However, kinetic analyses of the initial rate of 

 shortening and the final extent of shortening, for an eserinized nerve-muscle 



