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Maintenance of myocardial homeostasis critically depends on the ability of cardiac cells to adapt energy-dependent processes in response to metabolic challenge. This requires efficient monitoring of the cellular energetic status, secure delivery of information to energetic sensors and accurate translation of metabolic signals into cellular response. Although advances have been made in resolving the molecular identity of energy-response elements, mechanisms integrating metabolic sensor function with cellular metabolism are largely unknown. Sarcolemmal ATP-sensitive K+ (KATP) channels are prototypic membrane metabolic sensors, which act as bi-functional protein multimers combining catalytic with ion conduction properties. In the hetero-octameric KATP channel complex, the sulfonylurea receptor (SUR2A) harbors an intrinsic ATPase activity and confers fine nucleotide modulation of K+ permeation through the pore-forming Kir6.2 subunit. The metabolic sensor role of KATP channels stems from the non-equivalent properties of nucleotide binding domains (NBD1 and NBD2) in SUR2A. NBD1 binds nucleotides whereas NBD2 hydrolyzes ATP, yet cooperative interaction, rather than the independent contribution of each NBD, is critical for KATP channel regulation. The ATP hydrolysis cycle at SUR2A drives conformational transitions with distinct outcomes on channel gating to adjust membrane potential in response to intracellular metabolic oscillations. Nucleotide exchange between the channel ATPase and the cellular phosphotransfer network provides a mechanistic basis for coupling cell energetics with KATP channel gating. Disruption of phosphotransfer genes produces aberrant metabolic sensing by KATP channels, and generates a cellular phenotype with electrical vulnerability to metabolic challenge. Assigning to the channel catalytic module a role in integrating ion permeation with intracellular enzymatic pathways identifies a novel principle in the regulation of cellular excitability, and defines an operational paradigm for channel/enzyme multimers.

The ABCC2 protein, also designated the canalicular multispecific organic anion transporter (cMOAT) or multidrug resistance protein 2 (MRP2), belongs to the subfamily C of ABC transporter proteins (http://nutrigene.4t. com/humanabc.htm). It is now known that this subfamily comprises 12 members (Figure 1), including six MRP-related proteins (ABCCl-6, Cole et at. 1992; Paulusma et at. 1996; Taniguchi et at. 1996; Kool et at. 1997; Suguki et al. 1997; Lee et al. 1998; Kool et al. 1999; McAleer et at. 1999; Schuetz et at. 1999), the cystic fibrosis transmembrane conductance regulator (CFTR), and the sulfonylurea receptors SUR1 and SUR2. One of the major characteristics of subfamily C members is the relatively low sequence homology between their NH2-and COOH-terminal nucleotide binding domains (NBDs).

ATP-sensitive K+ channels (KAgp channels) were first described in cardiac myocytes (1) and were subsequently found in many other tissues including pancreatic 13-cells (25), skeletal muscle (6), smooth muscle (7), brain (8), pituitary (9), and kidney (10) and in mitochondria (11). KA,p channels were originally characterized by inhibition when the ATP concentration at the cytoplasmic surface was increased (12). It is now known that regulation of KATP channel activity is complex, involving factors including nucleotide diphosphates such as ADP, Mgt*, and phosphatidylinositol bisphosphate (13-18). KATP channels play important roles in endocrine cells, muscles, and neurones, by coupling metabolic state to membrane potential (12,19,20). In pancreatic 13 cells, KATP channels regulate glucose-induced insulin secretion. Inhibition of the KATP channels by glucose depolarizes the 13-cell membrane, leading to opening of the voltage-dependent calcium channels (VDCCs), and allowing calcium influx. The rise in intracellular calcium concentration ([Ca21) in the 13-cell triggers exocytosis of the insulin granules. While the K+ channel opener diazoxide inhibits insulin secretion by activating the KATP channels, sulfonylureas such as glibenclamide, which is widely used in the treatment of type 2 diabetes mellitus, stimulate insulin release by inhibiting the KATP channels (21,22) Fig1 The cloning of members of the inwardly rectifying K+ channel subfamily Kir6.0 and the sulfonylurea receptors has clarified the structure of KA,p channels and revealed a new paradigm of channel/receptor assembly.

Many different types of K+ channels are involved in cardiac electrical activity (Noble, 1965). Various depolarization-activated K+ channels (Kv channels) determine the shape of the cardiac action potential. Cardiac cells also contain Kir channels (Fig. 1) that are open at very negative potentials but show a reduced conductance at positive membrane potentials, a phenomenon termed inward, or anomalous, rectification (Fig. 2A; Katz, 1949). Work over the past 30 years has described three main types of Kir channel in cardiac tissue. (1) The classical inward rectifier, I K1, present in atrial and ventricular myocytes, shows “strong” inward rectification. Essentially no current flows through these channels at potentials positive to —40 mV (Noble, 1965; Vandenberg, 1994). (2) The KATP channel is found in ventricular, atrial, and nodal cells. KATP channels display “weak” rectification, allowing substantial outward current to flow at positive potentials (Noma, 1983; Nichols and Lederer, 1991). (3) The muscarinicreceptor-activated K + channel, K(ACh), is a strong inward rectifier found predominantly in atrial tissue (Bond et al., 1994). K(ACh) channels open in response to acetylcholine released from the vagus nerve and underlie the resultant slowing of the heart rate.

ATP-sensitive K+ (KATP) channels are recognized by their biophysical fingerprint, unique heteromultimeric structure, and distinct nucleotide-dependent regulation (Noma, 1983; Aguilar-Bryan and Bryan, 1999; Seino, 1999). These weakly inwardly rectifying, high-conductance, potassium-selective channels are kept closed by intracellular ATP and activated by intracellular ADP. Thereby, KATP channels set the membrane potential according to changes in the cellular metabolic state (Weiss and Venkatesh, 1993; O’Rourke et al., 1994; Dzeja and Terzic, 1998). KATP channels are distributed in the plasmalemma of various metabolically active tissues, including the heart (Noma, 1983), pancreatic β-cells (Ashcroft, 1996), skeletal (Vivaudou et al., 1991) and smooth (Quayle et al., 1997) muscle, and the brain (Spanswick et al., 1997). A related channel has been recognized in the inner membrane of mitochondria (Inoue et al., 1991; Paucek et al., 1992), underscoring the role of KATP channels in signaling networks that transduce intracellular metabolic events.

In cardiac myocytes, such as Purkinje fibers and ventricular myocytes, the depolarizing phase (phase 0) of the action potential is mediated by a rapid influx of Na+ ions through voltage-gated Na+ channels. A subsequent rapid, but incomplete, repolarization in phase 1is achieved by K+ efflux through transiently activated K+ channels. This early outward current sets the initial plateau potential, thus influencing the behavior of subsequently activated ion channels and the duration of the action potential. The plateau of the action potential (phase 2) is characterized by minimal net ion flow due to the balance between an inactivating Ca2+ inward current and K+ efflux through slowly activating voltage-gated channels. In phase 3, the K+ permeability increases with time and ultimately results in complete repolarization. In phase 4, the K+ permeability sets the deep resting potential, which governs the time period between action potentials. Therefore, K+ channels play essential roles in various phases of the cardiac action potential.

It is now 50 years since the accidental observations which indicated that a sulfonamide, p-amino-benzene-sulfamido-isopropyl-thiodiazole (2254 RP), could induce hypoglycaemia (Janbon et al., 1942). This response was shown to be due to stimulation of insulin secretion and led to the use of this class of sulfonamides (called sulfonylureas) to treat diabetes (Loubatieres, 1955; Bertram et al., 1955; Franke et al., 1955). Loubatieres (1944) also found that a related sulfonamide, 3-methy1-7-chloro-1,2,4-benzothiadiazine-1,1-dioxide (diazoxide) elicited hyperglycaemia, via inhibition of insulin secretion.