STRUCTURE OF NERVE CELL MEMBRANES 149 



be made; the blocking action of hexamethonium (C 6 ) should be enhanced if 

 the molecule binds by orientation (a) and one Me— group of N is replaced by 

 Et— since this change improves the fit at the anionic site; further Et— sub- 

 stitution will spoil the fit. For orientation (b), triethyl substitution would be 

 expected to yield an improved fit, because TEA just fits the interspace; the 

 chain length is too short for (c) to be considered, and as the presence of two 

 quaternary groups is essential for activity, (d) appears unimportant. The 

 results of experiment (Wien and Mason, 1953) are in agreement with orienta- 

 tion (a). The far more powerful receptor blocking action of Go cautions against 

 the conclusion that it orients in the postjunctional membrane in a manner 

 similar to C 6 in the ganglion. While it is true that Go has 4 more CH 2 groups to 

 enhance its binding, a conclusive indication of a basic difference in action is the 

 diminution in activity upon Et— substitution in the quaternary nitrogens, and 

 the marked species variability in sensitivity to Cm , suggesting a higher order 

 of specificity than that of many other blocking compounds. Hence (a) is ruled 

 out; orientation (b) seems unlikely because activity should be increased by 

 ethylation of the nitrogens; while (c) is indicated both because the chain length 

 gives a good fit, and because the result of binding two membrane molecules 

 together, as shown in Fig. 14 might be expected to be a depolarization resulting 

 from a disturbance of the normal packing. The selective action of Go is under- 

 standable because its insertion depends upon very large distances between 

 membrane molecules, and while chains that are too short cannot bind, chains 

 that are too long will tend to restore some of the disorder that is created. 



Curare and ACh are stated to compete for the same receptor; while this is 

 a summary of the results of experiment, it seems scarcely credible that such a 

 large and bulky molecule as curare (+)tubocurarine, has a molecular topog- 

 raphy even remotely similar to that of ACh. True, curare has 2 quaternary N 

 atoms at a distance very roughly two times the extended length of ACh but 

 they are on opposite sides of the molecule, a feature that makes any dual 

 interaction of this molecule with a surface rather unlikely. Nor, it is clear, are 

 two quaternary nitrogens necessary for selective receptor blocking; 0-eryth- 

 roidine with but a single tertiary nitrogen is an effective agent. Loewe and 

 Harvey (1952) have carefully examined the interquaternary distance concept 

 and found little in the way of support for it. From our model it is clear that 

 curare cannot orient in the interspace in any way other than with its long axis 

 parallel to that of the membrane molecules. While the distance between charges 

 in + - tubocurarine is 12.5 A., their separation from each other as measured along 

 the axis of the molecule is 10.A, precisely the separation in C 6 . The profile and 

 the orientation of these molecules is shown in Fig. 14, together with that of 

 /3-erythroidine. This latter substance is helpful in this analysis because it 

 illustrates that the peculiar shape of the molecule, one highly complementary 

 to that of the membrane molecules, can be a factor of importance in bringing 



