STRUCTURE OF NERVE CELL MEMBRANES 133 



experimental fact that compounds from G to C 5 are all equally good as general 

 anesthetics when concentrations for anesthesia are expressed as thermodynamic 

 activity. The observations mentioned about are best explained if (a) excitation 

 is a time-dependent process and one that requires a close fit between stimulating 

 molecule and membrane interspace, (b) there is some dispersion in the size 

 of interspaces in the membrane. Both these suggestions, in slightly different 

 form, have been used to explain changes in ion permeability of the membrane 

 and it therefore seems likely that the filling of a membrane channel with organic 

 molecules that fit closely, initiates the same transitory increase in Na + influx 

 as that produced by K+ At the top of Fig. 4 is shown the situation with respect 

 to fit for molecules of various sizes. Very small molecules not only may expect 

 to find few sites that fit, but will be distributed almost uniformly throughout 

 the membrane sites that are shaded in the diagram and indicate sites where 

 occupation results in narcosis. With very large molecules the situation is quite 

 different, the fact that most channels in the membrane are too small restricts 

 the distribution of such molecules to a few sites, and to even fewer that are 

 larger still. At the bottom of the diagram is shown the total number of sites 

 existing at various levels of interspace size, and the ratio of number of sites 

 that fit a molecule (within 0.5 standard deviation) to the total number of sites. 

 Clearly as molecular size increases so does the probability that the molecule 

 will occupy a channel that it fits. Stated another way, as molecular size increases 

 so does the specificity of the membrane with respect to the shape of the mole- 

 cules that it will admit. 



If, instead of considering paraffins, and spherical molecules, we have ir- 

 regularly shaped molecules with strong polar groupings, a very large number of 

 further complications are introduced. The nature of these difficulties can only 

 be hinted at; they involve dealing with the problem of what fraction of the 

 molecules arriving at the membrane are properly oriented for penetration, of 

 the penetrating molecules how many are properly oriented for binding to 

 specific points within the interspace, whether reorientation can take place 

 within the interspace, and the estimation of the binding strength and chemical 

 stability of molecules in the membrane. The halogenated insecticides provide 

 a convenient transition from ideal molecules to the intensely complicated situa- 

 tion with highly polar molecules. 



A remarkable series of compounds exist in the isomers of hexachlorcyclo- 

 hexane (sometimes called benzene hexachloride or BHC). They result from 

 interchanges between chlorine and hydrogen on a cyclohexane ring, and are, 

 in effect, changes in the shape of the molecule without changes in the total 

 number of atoms. Only one isomer, the 7, is a strong convulsant both in insects 

 and mammals, and one isomer, the 5, has appreciable narcotic potency. It has 

 been possible to explain this peculiar behavior on the basis of the model of the 

 membrane, with the additional assumption that convulsant activity is caused 



