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 nonselective 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 KNa currents) in native neurons. Human mutations in Slack channels produce extremely severe defects in learning and development, suggesting that KNa channels play a central role in neuronal plasticity and intellectual function. 1. Introduction A key determinant of the many varied types of firing patterns that can be observed in excitable cells is the number and types of potassium channels that are expressed in the plasma membrane. In contrast to the relatively low number of genes for other channels that regulate excitability (10 known genes each for voltage-activated sodium and calcium channels), there are at least 77 known genes that encode alpha subunits of potassium channels [1]. Moreover, in contrast to sodium and calcium channels, in which the entire pore-forming channel is formed from one polypeptide, most potassium channels are tetramers that result from the coassembly of either the same or different subunits from the same family. This finding, coupled with the fact that most potassium channel genes have multiple splice isoforms and that the subunits themselves are subject to a variety of posttranslational modifications, means the potassium channel superfamily is capable of producing an extraordinarily large variety of channels with different kinetic behaviors and voltage dependences. The pore-forming α-subunits of potassium channel can be divided into voltage-dependent (Kv) subunits, inward rectifier (Kir) subunits, two pore (K2P) subunits (which assemble as dimers rather than tetramers), those activated by intracellular calcium (KCa subunits), and those activated by intracellular sodium (KNa subunits). While the existence of KNa channels has been recognized since the early 1980s, it is only in the last ten years or so that their molecular identity has been known. Research over this time has revealed that rather small changes in the function of these channels can have devastating effects on neuronal development and intellectual function [2, 3]. This review will summarize our current understanding of this class of
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