LAUSR

We thank Kotler et al. (1) for their response to our paper in PNAS (2). Kotler et al. (1) are correct that the Goldman–Hodgkin–Katz (GHK) formulation (3, 4) is often more appropriate when the ionic concentrations are changing, because ion channel conductance varies with the concentration of the permeant ions (5–7). This is often underappreciated because of the historical success of Hodgkin–Huxley’s ohmic formulation (8), as the properties of the squid axon obviated many of the conditions that would ordinarily call for the GHK equations (5–7). Most selfrespecting biophysicists would prefer to study ion channel permeation and conductance under symmetric ionic conditions, thus removing the rectification caused by asymmetries in ionic concentrations that would call for the use of the GHK equations. But there are also conditions in which the GHK formalism has important limitations, some of which decrease the difference between results of the GHK and ohmic models (5). As outstandingly successful as the Hodgkin–Huxley (8) formulation has been for the entire field, there are conditions in which the GHK formulation may be better, assuming that one would have a way to estimate the relative limitations of the GHK and linear models in relatively complex geometries or circuit contexts. Kotler et al. (1) argue that the problem we studied in Zang and Marder (2) would have been better modeled by GHK than the ohmic mode. In Fig. 1, we show that the qualitative effect we report is preserved using the GHK formalism. Fig. 1 makes the additional point that the large pump current plays a key role in the phenomena we report. Our goal was to point out the differences in the profile of Na ion concentrations in the myelinated and unmyelinated axons of various diameters, and to highlight the important effects of the cable structure and the Na/ K pump on resilience. Thus, as intuited by Kotler et al. (1), the essential messages of our paper are preserved independently of how the Na currents