5 Nicholls.indd NS NEW .indd

Action potentials, which define electrical excitability, depend on the activity of voltage-gated Na, Ca and K (Kv) channels (see the review in this issue by Sanguinetti and Tristani-Firouzi, p. 463). But electrical activity without modulation would be like an automobile with one speed, no steering and no brakes. In addition to the channels that play the leading parts, bio-electric signalling involves many crucial bit players (see the review in this issue by Miller, p. 484) that provide essential gears, steering and brakes. These include a family of K channels, the so-called inward rectifier (Kir) channels, which lack steep voltage-gating. By stabilizing the resting membrane potential, these channels act as a brake on excitability. One member, the KATP channel, modulates electrical activity in multiple tissues. In a complex interplay of mechanisms, the KATP channel is inhibited by the non-hydrolytic binding of ATP, but activated by interactions with Mg-bound nucleotides (Mg-nucleotides) at separate sites. The inhibitory effect dominates, and channels are closed, when cellular phosphorylation potential is high, but as metabolism decreases, the activating effect wins out and channels open. In this way, the channel provides a unique electrical transducer of the metabolic state of the cell. What mechanisms of channel regulation allow this transduction? Many questions remain to be addressed, but as discussed below, the cloning of constituent subunits of the KATP channel and the crystallization of structurally related proteins have provided the raw materials to gain a detailed understanding of how nucleotides interact with the KATP channel and an explanation of the molecular basis of channel activity and of channel-dependent human disease.