How to Lose Your Hippocampus by Working on Chloride Channels

Previews result of defective endosomal acidification (Piwon et al., Prior to the elucidation of the CLC genes, electrophys-iologists had characterized a number of chloride currents roughly divided into voltage activated (ClC-1 being the firmly established and responsible member), calcium Chloride channels are the problem children of ion chan-activated, and swelling activated. With the discovery nels. By comparison, the well-behaved K ϩ , Ca 2ϩ , and of Cl channel genes, experimentalists have been busy Na ϩ channels are understood to high levels of precision, trying to match the known currents with their molecular with most of the remaining questions surrounding the counterparts. But a number of problems unique to Cl detailed movements of their amino acids during gating. channels have led to a murky functional subclassifica-Even the holy grail of ion channels, the structural mecha-tion. First, intracellular Cl concentrations are not as nism of cation selectivity, has largely been laid to rest firmly set as many cations, yielding a range of Nernst by crystallography, while the chloride channels continue potentials from Ϫ15 to Ϫ65 mV. Selectivity between to provide confounding results at the level of site-halide ions (F, Br, Cl, I) is low and, although used to try directed mutagenesis. In this issue of Neuron, a knock-to distinguish channel types, is prone to error. Chloride out (KO) mouse of one chloride channel subtype reminds channels are ubiquitous—no mammalian cell or cell line us of the importance of this recalcitrant group of chan-is known to lack them. There are no highly specific toxins nels (Stobrawa et al., 2001). Stobrawa, Jentsch, and or small molecule blockers. Whole-cell Cl Ϫ channel ki-colleagues, in attempting to straighten out a controversy netics are confusingly similar and, since many are regu-surrounding the role of swelling-activated chloride chan-lated by nucleotides and kinases, slowly change with nels, knocked out the ClC-3 gene and stumbled across time. Finally, Cl Ϫ channels may be heteromultimers of the way to completely eliminate the hippocampus. But Cl Ϫ channel protein subunits. The presence of numerous the paper is a double-edged sword that will also open and complex Cl Ϫ currents in the common expression the veins of controversy surrounding swelling-activated system, Xenopus laevis oocytes, has misled many inves-chloride channels. tigators into confusing their newly minted clones with Ion channels are electrical switches that rapidly intrinsic currents. One of the most sought-after Cl chan-change transmembrane voltages. In doing so, they are nels is …