Gating Mechanism of KATP Channels

Based initially on their prominence in the squid giant axon, their useful pharmacology, and subsequently on being the first cloned K channels, voltage-gated K (Kv) channels have received the lion’s share of attention to their biophysical properties. Kv and Ca-activated K channel kinetics and gating mechanisms have been analyzed, and modeled, in exquisite detail (Hille, 2001). Inward rectifier K (Kir) channels have received less attention, and perusal of the literature indicates that there is still no common understanding of kinetic mechanisms in Kir channels. It is our contention, however, that one is in reach. Amongst Kir channels, ATPsensitive (K ATP ) channels are uniquely regulated by cytoplasmic nucleotides and specific pharmacological agents. As such, they play a critical role in coupling cellular metabolism to electrical activity, and are major drug targets in pancreatic, vascular smooth muscle and cardiac muscle (Ashcroft, 1988; Nichols and Lederer, 1991). We would argue that these unique properties also permit elucidation of important features of channel gating that are relevant to the whole class of Kir channels. The molecular mechanisms of K ATP channel regulation have occupied many groups for the last twenty years. Kinetic measurements have led to mathematical models of gating, mutagenesis has indicated relevant molecular elements, and crystallization of various K channel subunits and domains now provides templates for the channel structure. Distilling a consistent model of channel activity and regulation from this broth of data is the challenge for the field, and the topic of this Brief Review. The K ATP channel is formed from four Kir6.2 pore– forming subunits, and four regulatory sulfonylurea receptor (SUR) subunits (Clement et al., 1997; Inagaki et al., 1997; Shyng and Nichols, 1997) (Fig. 1). Activity is modulated by voltage and by multiple ligands, including ATP and PIP 2 , which act on the Kir6.2 subunits themselves, as well as sulfonylureas, potassium channel openers, and Mg-nucleotides, which act on the SUR subunit. Inhibitory ATP binds to the Kir6.2 subunit, while MgATPand ADP-activation results from interaction with the SUR subunits (Matsuo et al., 1999, 2000; Tanabe et al., 1999; Ueda et al., 1999; MacGregor et al., 2002; Vanoye et al., 2002). K ATP channel behavior is undoubtedly complex, and at present a complete kinetic model of channel activity, including pharmacological regulation through the SUR subunits is impossible. However, we will argue that a consistent model of Kir6.2 channel activity does arise, and that from this model, the additional complexity of heteromeric complexes will ultimately emerge. We will first consider how thermodynamic and kinetic measurements lead to a model that can explain gating, then consider the structural basis of this behavior.