Large conductance calcium-and voltage-activated K+ channels (Slo1), also referred to as “BK” or “maxi K” channels because of their high single channel conductance (250–300 pS in symmetrical 150 mM KCl), are widely distributed in many different tissues (Kaczorowski et al., 1996). A signature feature of BK channels, in addition to their high K+ selectivity and conductance, is that they are activated in a highly synergistic manner by both intracellular calcium ion (Ca2+ i) and depolarization (Marty, 1981; Pallotta et al., 1981; Barrett et al., 1982; Latorre et al., 1982). This is shown in Fig. 1, which plots channel open probability Po (z axis) versus Ca2+ i (y axis) and membrane potential (x axis). It is this synergistic activation that allows BK channels to play key roles in controlling excitability in a number of systems, including regulating the contraction of smooth muscle, the tuning of hair cells in the cochlea, and regulation of transmitter release (Robitaille et al., 1993; Ramanathan et al., 1999; Brenner et al., 2000; Wang et al., 2001). It is also this synergistic activation together with the high single-channel conductance and the infrequent gating transitions to subconductance levels that has made the BK channel such an attractive subject for the study of gating mechanism. The dual activation of the channel allows the Po to be biased into optimal ranges for the study of activation by either voltage or Ca2+ i by appropriate setting of the other parameter. This review will focus on this author’s highly biased view of some of the key experiments and observations that have helped formulate our current concept of how BK channels gate. Due to space limitations, the modulation of the gating by ß subunits is not included, and most of the papers to be discussed will be recent papers that are providing the final flashy assault to the summit, rather than the earlier studies providing the crucial stepwise slog up the mountain. The progress toward understanding how BK channels gate is based on three complimentary and essential approaches: kinetic analysis, molecular biology, and 3-D structure. The greatest progress has been made on kinetics and molecular biology. There is not yet a structure of BK channels, but there are structures of related K+ channels from bacteria. BK channels are tetramers (Shen et al., 1994). A schematic diagram of one of the four α subunits that assemble to form functional channels is shown in Fig.

2. Similar to the superfamily of voltage gated K+ channels (Butler et al., 1990; Isacoff et al., 1990; Wei et al., 1990), BK channels contain transmembrane segments S1–S6, including an S4 voltage sensor and a P region to form the selectivity filter of the pore (Adelman et al., 1992; Butler et al., 1993; Diaz et al., 1998; Cui and Aldrich, 2000). In addition, BK channels have an S0 segment that places the NH2 terminus extracellular (Meera et al., 1997) and a very large intracellular COOH terminus that contains more than twice the number of amino acid residues that are contained in S0–S6 (Adelman et al., 1992; Butler et al., 1993). Wei et al.(1994) found that they could cut the channel at an unconserved linker between S8 and S9 (see Fig. 2) and then express functional channels from the separate cores and tails. The core can be further subdivided into the transmembrane segments S0–S6 and an intracellu-