The Cole-Moore Effect: Still Unexplained?

Abstract

In the first issue, on the first page of the Biophysical Journal in 1960, Cole and Moore provided the first confirmation of the Hodgkin and Huxley formulation of the sodium and potassium conductances that underlie the action potential. In addition, working with the squid giant axon, Cole and Moore noted that strong hyperpolarization preceding a depolarizing voltage-clamp pulse delayed the rise of the potassium conductance: once started, the time course of the rise was always the same but after significant hyperpolarization there was a long lag before the rise began. This phenomenon has come to be known as the Cole-Moore effect. Their article examines and disproves the hypothesis that the lag reflects the time required to refill the membrane with potassium ions after the ions are swept out of the membrane into the axoplasm by hyperpolarization. The work by Cole and Moore indirectly supports the idea of a membrane channel for potassium conductance. However, the mechanism of the Cole-Moore effect remains a mystery even now, buried in the structure of the potassium channel, which was completely unknown at the time.

Figure 1

Predictions of n, n⁴, n⁶, and n²⁵ models. The probability of full activation is shown as a function of time. In each model, the carrier was assumed to be fully at rest before the depolarization onset. The near horizontal segments immediately after depolarization represent the lag, which is absent in the n model and longest in the n²⁵ model. To see this figure in color, go online.

Figure 2

Plausible resting and activated conformations of the S4 voltage sensor domain. The relevant residues are labeled using the numbering of the K_V1.2/2.1 chimeric channel (27) and of the Drosophila Shaker channel in parentheses. Adapted from Hoshi and Armstrong (33). Also see Jensen et al. (32) and Vargas et al. (34). To see this figure in color, go online.