Return of the Electric Binding Site

The BK-type Ca 2+-activated K + channel has been the subject of increasingly detailed mechanistic study since the fi rst recordings of this channel were obtained more than 25 years ago (Pallotta et al., 1981 ; Latorre et al., 1982 ; Magleby, 2003 ; and references therein). But if you thought that our understanding of the gating of the BK channel and its allosteric regulation by Ca 2+ and trans-membrane voltage had reached its summit, then once again you would be wrong. In a remarkable display of patch-clamping and kinetic analysis appearing in this issue, the bear is poked once again, with this iteration of analysis constrained by high-resolution Ca 2+ dose-response curves, containing data at 22 (!) different [Ca 2+ ]. Here, Sweet and Cox (see p. 491) analyze the two high-affi nity Ca 2+ binding sites of the BK channel using mutations to selectively disable each site, and obtain defi nitive results on how the sites behave in isolation and how they might interact with one another in the intact BK channel. A surprising fi nding is that binding to one of the two binding sites is modulated by transmembrane voltage. This intriguing twist opens possibilities for identifying a structural basis for interactions between the voltage sensor and one of the principal Ca 2+ activation sites of the channel. Despite the functional simplicity of the BK channel, which is activated principally (for the purpose of this Commentary) by cytoplasmic Ca 2+ and depolarization, and our high level of understanding of the mechanisms underlying its activation, there are still many intricacies of this channel that are not well understood. And these details are not trivial; because BK channels serve as cyto-plasmic Ca 2+ detectors that can rapidly respond to and modulate transmembrane voltage, they are critical in controlling action potential fi ring in some neurons, and they are also important in the feedback loop controlling smooth muscle contractility (Brayden and Nelson, 1992 ; Brenner et al., 2000, 2005). So the mechanism by which BK channels sense and respond to cytoplasmic [Ca 2+ ] is of interest. Although many of the side chains that are functionally important in Ca 2+ sensing have been revealed by mutagenesis combined with careful electrophysiologi-cal measurement (Bao et al. et al., 2005), we must acknowledge that we do not yet know which residues coordinate Ca 2+ in the BK channels, nor do we know the …