STRUCTURE OF NERVE CELL MEMBRANES 141 



than is the enzyme. It is also apparent that resistance to DDT can be obtained 

 in other ways: the interspaces may be too small for a fit, or local alterations in 

 the surfaces of membrane molecules may result in changes in the surface 

 roughness that prevent penetration. 



The Enzyme Hydrolyzing Acetylcholine 



Certain of the features developed in analyzing the relationship between 

 DDT and DDT-ase suggest that a comparison with acetylcholine (ACh) and 

 its enzyme ACh-ase might contribute further information of value in the 

 analysis of membrane structure. At the outset it must be emphasized that 

 owing to flexibility of the ACh molecule, and to certain peculiar relationships 

 between inhibitors of either the receptor or the enzyme, information on the 

 nature of the ACh system must of necessity be much more tentative than that 

 for DDT. Because of the high order of complexity that is involved, experimental 

 data are almost invariably subject to more than one interpretation; this fact 

 puts a premium on explanations that can interrelate observations involving a 

 wide variety of chemical or physical treatments. 



The principal means of distinguishing receptor from enzyme in the ACh 

 system is the differential action of certain drugs and substrates. Thus there 

 are drugs that block the activity of the esterase and enhance the activity of 

 the receptor, presumably by allowing ACh to remain in contact with the recep- 

 tor for longer periods of time, while on other tissues the same inhibitor blocks 

 both receptor and enzyme action. Again, there are drugs that block receptor 

 activity without depressing the activity of the enzyme. Substrates for the 

 esterase also have a differential action on the receptor; thus dimethylaminoethyl 

 acetate is a good substrate and a poor stimulator of the receptor, while the 

 reverse is true for butyrylcholine. Perhaps the first question to be asked is 

 whether there is a role of physiological significance that can be assigned to 

 ACh-ase at, for example, the neuromuscular junction (n-m-j) of twitch-pro- 

 ducing muscles. While localization of the enzyme close to the cell membrane 

 appears likely (Hellmann, 1952), we are left in doubt as to which of three 

 general arrangements actually exists: (a) the enzyme is just outside the cell 

 membrane, (b) it is just inside the cell, or (c) the membrane is a mosaic of 

 areas of enzyme and receptor. Arrangement (a) would serve mainly to at- 

 tenuate the material reaching the receptor, and would require larger signals 

 from the pre-junctional fibers; it might be thought of as sharpening the chemical 

 signal by reducing low concentrations of ACh to subthreshold values and being 

 overwhelmed by larger concentrations. This arrangement requires ACh-ase 

 to be present in low concentrations and seems therefore unlikely. Arrangement 

 (b) would be presumed to prevent the back diffusion of ACh once it has passed 

 through the membrane and presumably exerted its physiological effect; there 



