Commentary Knocking on Channel's Door The Permeating Chloride Ion Acts as the Gating Charge in C1C-O

The well known chloride channel from Torpedo has been a round since 1979 (White and Miller, 1979), but it continues to supply us with new surprises. In this issue of The Journal of General Physiology Chen and Miller analyze in great detail the voltageand chloride-dependent activation mechanism of the peculiar "double-barreled" channel (Chen and Miller, 1996), which turns out to be completely different f rom that of the more familiar voltage-dependent cation channels. The Torpedo chloride channel had been discovered by Chris Miller and colleagues in their attempts to study reconsti tuted acetylcholine receptors from Torpedo electroplax (see Miller and Richard, 1990 for review). Instead of the nicotinic receptor, they consistently observed a voltage-dependent C1selective channel. Miller cont inued to characterize the chloride channel in lipid bilayers and revealed several important aspects of its function. The channel opens in bursts and within each burst two equidistant conductance levels are seen. The gating of the two conductance levels can be almost perfectly described assuming two separate and independen t conduct ion pathways. Single "protopores" are activated at positive voltages (fast gate) whereas the occurrence of bursts is favored at hyperpolarized voltages (slow gate) (Miller and Richard, 1990). This "double-barreled model" was supported by experiments in which individual protopores could be inhibited by DIDS 1 (Miller and White, 1984), a blocker of C1C-0 when applied intracellularly. An additional feature of C1C-0 is that its gating is evidently coupled to the electrochemical gradient of chloride. This coupling was inferred indirectly from a violation of microscopic reversibility in channel gating, observations greatly facilitated by the double-barreled structure of the channel (Richard and Miller, 1990). If history had stopped at that point one would have been left with a biophysically interesting but possibly exotic fish channel that was probably unimpor tant for