586 ANNALS NEW YORK ACADEMY OF SCIENCES 



second (perhaps even in a few microseconds, which Cole has mentioned 

 as a more appropriate time for the impedance changes in nerve), and 

 that the enzyme activity in the C.N.S. would split a layer covering 

 10^ sq. mu. per gm., are impressive. There is no question of strong 

 esterase activity. However, it is worth noting, for the C.N.S., that 

 even the surface of the nuclei in a gram of brain, let alone the whole 

 neuronal surface, is some 4 X 10^° sq. mu.'^'' The difficulties appear 

 when one examines the rest of the system, to see how well it can keep 

 'up with the esterase. Let us assume, with Nachmansohn, that some 

 2000 cal/M are required to esterify choline to ACh, and calculate, from 

 his data on enzyme content, Feldberg's summary'^ of ACh content and 

 liberation, and the figures of myself and others on heat and metab- 

 olism, the over-all balance for nerve and brain. 



Nachmansohn estimates that, in mammalian brain, ChE can split up 

 to 10"^ molecules of ACh per millisecond per gram fresh tissue. This 

 amounts to 6 millimoles per hour per gram. In terms of Qcit: values, 

 reduced to these same units (mM, hr, gm.), less ACh could be split: 

 between 0.3 mM for cortex, and 3.0 for caudate nucleus or sympathetic 

 ganglia. For mammalian nerve, the rate calculates to 0.06; for frog 

 nerve (20°), to 0.05; and for white matter, to 0.02. In contrast, the 

 maximum rate of ACh synthesis (in tissue brei in N., with ATP and 

 all necessary accessories) is 0.001 mM for mammalian brain and 0.0005 

 for nerve, still in these same units. In both mammalian brain and 

 nerve, therefore, ChE activity is over 1000 times, perhaps over 5000 

 times, as great as ChA activity, and similar relations will probably be 

 found for the frog. Neural enzymes can split ACh by three or four 

 magnitudes faster than they can build it. 



This calculation is made, of course, for maximum rates and over long 

 time intervals, and requires further consideration. If, for example, the 

 synthesis normally continues evenly in time, but the hydrolysis occurs 

 only in brief bursts associated with activity, the discrepancy in rates 

 might be unimportant. But this will not hold. First, whether ACh be 

 associated with the potential or impedance changes of a nerve action, 

 the rise is far more rapid than the fall, and the need for an explosive 

 release of the agent is even more imperative than for an explosive de- 

 struction. If, therefore, ACh is synthesized and destroyed in the 

 course of each nerve action, ChA should actually be several-fold more 

 active than ChE, instead of a thousand-fold less active. Let us make 

 the more favorable assumption, however, that ACh need not actually 

 be synthesized for each impulse, but only be released from a store. 

 Then, though used in bursts, its formation could be continuous. Even 

 so, there remain fatal discrepancies. 



