Where’s the gate? Gating in the deep pore of the BKCa channel

133 C o m m e n t a r y Four -helical segments at the intracellular entrance to the ion conduction pathway splaying open is the conventional imagery of a K + channel opening to allow K + ions and co-traversing water molecules to hop through the channel's pore (Fig. 1) (Armstrong, 2003; Swartz, 2004). This view of K + channel gating—already depicted in numerous textbooks—has been derived largely from K + channel crystal structures published over the last decade , most notably of the voltage-independent 2TM K + All of these structures display in the outer third of their pore regions a structurally conserved K + selectivity filter (Doyle et al., 1998), whose form is consistent with many previous functional measurements and presents a unified picture of K + selectivity (Armstrong, 2003). Exquisite K + selectivity contemporaneous with a high transport rate is achieved via the precise arrangement of oxygen atoms so as to optimally coordinate multiple dehydrated K + ions as they pass single file through the se-lectivity filter separated by intervening water molecules (Armstrong, 2003). Have these structures also lead us to a unified theory of activation gating? At first it appeared so. Comparisons, for example, of the crystal structures of KcsA, a closed-channel structure, and MthK, an open-channel structure , reinforced the notion, developed from Cd 2+-bridging experiments with the Shaker K + channel (Holmgren et al., 1998), that the main ion conduction gate of K + channels (" activation gate ") is formed by the bundle crossing of the inner portion of the four pore domain helices (Fig. 1 A). Indeed, in the KcsA structure, this region narrows to less than the dehydrated diameter of a K + ion (2.66 Å), apparently forming an ion and watertight seal, whereas in the MthK structure, the pore at the bundle crossing has a diameter of 12 Å (Jiang et al., 2002), more than sufficient to allow hydrated K + ions to readily pass. Thus, these types of comparisons, in conjunction with experiments that demonstrated that in the closed Shaker channel the bundle crossing also forms an ion and watertight seal (del Camino and Correspondence to Toshinori Hoshi: hoshi@­hoshi.org Yellen, 2001; Kitaguchi et al., 2004), lead to the following standard view of K + channel activation gating. The activation gate of the K + channel is formed by the bundle crossing of the inner pore helices. The …