The mechanism of cellular resting potential according to the association-induction hypothesis and the perfused squid axon: correcting a misrepresentation.

In 1968, in the lead article of the 48th volume of Physiological Reviews,' P. C. Caldwell cited work on internally perfused squid axon as creating "difficulties for theories due to . . . Ling (185-187 [in this paper, ref. 2-41)." Caldwell stated in his article: "The difficulties raised for Ling's fixed-charge hypothesis (185-187) are . . . fairly fundamental. This hypothesis implies that ions are held in cells in concentrations differing from those in the external medium by selective interaction with fixed, charged sites on cytoplasmic proteins rather than by selective permeability processes and active transport in the cell membrane. It is very difficult to see how this hypothesis could be made to account for the apparently normal resting and action potentials of perfused squid axons from which the natural axoplasm has been removed, since the perfusion fluids are simple salt solutions containing no large polyanions capable of selective adsorption of cations." In the years following the publication of his article, Caldwell's criticism has often and sometimes quite faithfully been echoed by other reviewers and scientists (e.g., ref. 5 and 6) and has, therefore, been considerably influential in the adverse opinions about the Association-Induction Hypothesis. It is the purpose of this note to point out that these difficulties found by Caldwell arose entirely from his failure to grasp the essence of the theory he criticized. The three publications bearing my name and cited by Caldwell in his review were presented over a period of ten years. The first, published in 1952, introduced the hypothesis that later gained the name of the "Fixed-Charge Hypothesis"; the second, published in 1960, gave the hypothesis a revised name, the "Fixed-Charge-Induction Hypothesis"; in the last cited publication, my 1962 monograph, the hypothesis assumed its final title, the "Association-Induction Hypothesis." The name "Fixed-Charge Hypothesis" had been abandoned for eight years by the time Caldwell published his review. However, his misunderstanding was not limited to the use of an outdated name. The Fixed-Charge Hypothesis was primarily concerned with the mechanism of selective accumulation of K+ in living cells. The subsidiary theory of cellular electric potential was