NACHMANSOHN: CHEMICAL MECHANISM IN NERVES 397 



known to occur in living cells, which could not be followed by direct 

 chemical determination of the compounds metabolized. Especially for 

 an event occurring with such a high speed as the propagation of the 

 nerve impulse, analysis of the enzyme systems involved appeared to be 

 the most promising approach. 



Enzyme studies alone are, however, not sufficient for the elucidation 

 of a biological mechanism, since there are so many simultaneous enzy- 

 matic reactions in the complex system of the living cell. It is necessary 

 to correlate enzyme activities with events in the intact cell recorded 

 by physical methods. The most conspicuous example of such an ap- 

 proach is the development of muscle physiology. Through the pioneer 

 work of A. V. Hill and 0. Meyerhof, many physical and chemical 

 changes have been correlated, and our concept of the mechanism of 

 muscular contraction has, according to an expression of A. V. Hill, 

 gone through a real "revolution." 



The question of the role of ACh in the mechanism of nerve activity 

 has been approached by the study of the enzyme systems involved in 

 the formation and hydrolysis of the ester. On the basis of their be- 

 havior in vitro, the activities of the enzymes could be correlated in dif- 

 ferent ways with events in the living cell recorded by physical methods. 

 The facts established show that the original theories of the role of ACh, 

 and, more generally, the idea of "chemical mediation," have to be mod- 

 ified. There is a strong body of evidence that the release and re- 

 moval of ACh is an intracellular process, occurring at points along the 

 neuronal surface and directly associated with the nerve action poten- 

 tial. The agent, however, which transmits the impulse along the axon, 

 as well as across the synapse, is the action potential.*'"^ Some of the 

 most important features of these investigations may be briefly outlined. 



I. CHOLINESTERASE 



A. Time Factor 



ACh is inactivated by the enzyme cholinesterase, which hydrolyzes 

 the ester into choline and acetic acid. The first essential result of the 

 studies of this enzyme has been the evidence of its high concentration 

 in nerve tissue: Significant amounts of ACh may be split in milli- 

 seconds; that is, a period of time of the order required for the passage 

 of a nerve impulse. Consequently, the potential rate of ACh metab- 

 olism is thus sufficiently high to permit the assumption that it parallels 

 the rate of the electric changes and may, therefore, be directly con- 

 nected with the nerve action potential. 



