Slack, Slick and Sodium-Activated Potassium Channels

Abstract

The Slack and Slick genes encode potassium channels that are very widely expressed in the central nervous system. These channels are activated by elevations in intracellular sodium, such as those that occur during trains of one or more action potentials, or following activation of non-selective cationic neurotransmitter receptors such as AMPA receptors. This review covers the cellular and molecular properties of Slack and Slick channels and compares them with findings on the properties of sodium-activated potassium currents (termed K_Na currents) in native neurons. Human mutations in Slack channels produce extremely severe defects in learning and development, suggesting that K_Na channels play a central role in neuronal plasticity and intellectual function.

Figure 1

Schematic diagram of a Slack K_Na channel subunit depicting the relative positions of the two RCK domains, consensus PKC phosphorylation sites (depicted simply as red numbers corresponding to the positions of the amino acids), the position of the regulatory PKC site Serine 407, and the positions of the two characterized mutations that give rise to malignant migrating partial seizures of infancy (blue) (modified from [2]).

Figure 2

Activation of Slack and Slick channels by cytoplasmic sodium. (a) Representative patch of macroscopic Slack currents recorded at 0 and −80 mV in an excised inside-out patch from Slack-transfected CHO cells in the presence and absence of 90 mM sodium. (b) Concentration-response relationship of sodium activation of Slack current in excised patches. Currents were normalized those recorded in 90 mM sodium. (c) Excised patch recording at −80 mV from a CHO cell transfected with Slick. The cytoplasmic face of the patch was perfused with a solution containing either 0 or 50 mM intracellular sodium. (d) Concentration-response relationship of sodium activation of Slick channels in excised patches. Figures modified from [4].

Figure 3

NAD⁺ increases the sodium sensitivity of K_Na channels excised from adult rat dorsal root ganglion neurons. Concentration-response relationship provides estimates of EC₅₀ for sodium activation of 50 mM and 17 mM in the absence and presence of NAD⁺, respectively. Figure modified from [5].

Figure 4

FMRP alters gating of Slack-B channels in inside-out patches. (a) Recording of a patch containing 3-4 Slack channels before, during and after transient application of FMRP(1–298) to the cytoplasmic face of the patch. Top traces show representative 10 s examples of recording at −40 mV and bottom traces show expanded time views of the same patch. Arrows marked S indicate the occurrence of subconductance states that are suppressed by FMRP(1–298). (b) All-points amplitude histograms of Slack channel activity plotted on a logarithmic scale before and after application of FMRP(1–298) and after washout. C marks the closed state, S indicates subconductance states, and numbers on peaks in the histograms refer to the number of fully open Slack channels. Modified from [6].