Balanced Diets Include Carbohydrates, Proteins, and Fats

In addition to the steep voltage-dependent K 1 currents that play a role in repolarization of the heart, two major K conductances control the resting potential. The classical strong inward rectifier (IK1) is constitutively active and acts to stabilize the resting potential. During depolarization, the strong rectification of IK1 significantly reduces conductance, permitting a long action-potential plateau. The ATP-sensitive potassium current (IK,ATP) is not usually active, but the density of underlying channels is so high that when activated in conditions of metabolic inhibition, such as ischemia, the action potential is massively shortened and the ventricle eventually becomes inexcitable. Although this channel was named for its defining property of inhibition by ATP, it is far from clear what signals actually lead to channel opening in physiological and pathophysiological conditions. A central paradox is the following: in excised membrane patches, KATP channels are half-maximally inhibited by '10 to 50 mmol/L ATP, but intracellular [ATP] does not fall below millimolar levels except under very extreme conditions.1 It has long been recognized that MgADP and MgGDP act as antagonists to ATP inhibition of the channel,1 and the cloning and expression of the relevant SUR and Kir6 subunits of the channel2 have revealed details of this antagonism. ATP inhibition occurs through a direct interaction with the poreforming Kir6 subunit; Mg-diphosphate activation of the channel occurs through interactions with the nucleotidehydrolyzing domains of the SUR subunit (Figure). Both experiments and computer modeling indicate that the degree of activation of IK,ATP conductance that is observed in ischemia or metabolic inhibition may be achieved by the stimulatory effects of elevated Mg diphosphates in the maintained presence of ATP.3–6 In addition, the disease-causing effects of channel mutations that specifically abolish diphosphate stimulation of pancreatic KATP channels support this concept.7,8 However, there have remained some intriguing and unexplained observations regarding native cardiac channels, and new, extremely potent modulators of channel activity have appeared to additionally complicate the picture and bring new possibilities to channel regulation. Findlay and Faivre9 tested the ATP sensitivity of ATP-sensitive KATP channels in rat ventricular myocytes and found that in 102 inside-out patches, the half-maximal inhibitory concentration of the channels varied as much as 60-fold. This variation in ATP sensitivity is not experimental error, indicating either that different molecular species must underlie the variation or that ATP sensitivity is dynamically variable. It is now widely accepted that the cardiac channel–forming isoforms are Kir6.2 and SUR2A,10 although there is evidence of expression of both Kir6.1 and SUR1 in ventricle.11,12 However, recent studies have demonstrated dramatic effects of both protein modification and of lipids in controlling channel activity.