Dept. of Biochemistry and Molecular Biology
Oregon Graduate Institute of Science & Technology
The ATP-sensitive potassium channel from the inner mitochondrial membrane (mitoK [subscript ATP]) is highly selective for conducting K+ ions and is inhibited with high affinity by ATP. The primary function of this channel is regulation of mitochondrial matrix volume. Any net K+ flux across the inner mitochondrial membrane is accompanied by electroneutral flux of anions and osmotically obligated water. Electrophoretic K+ uptake into the matrix is conducted through mitoK [subscript ATP] and K+ leak, while K+ efflux is mediated by the electroneutral K+/H+ antiporter. Net K+ flux has little effect on matrix K+ concentration, which is about 180 mM, but does have a significant effect on matrix volume. The objective of this project was the investigation of the physiological and pharmacological properties of mitoK [subscript ATP]. Measurements of K+ flux enabled characterization of the biochemical properties of mitoK[subscript ATP] through either purified mitoK[subscript ATP] reconstituted into liposomes or bilayer lipid membranes or mitoK[subscript ATP] in intact mitochondria using light scattering. Using these models, it was possible to demonstrate that mitoK[subscript ATP] is activated by guanine nucleotides and K[subscript ATP] channel openers, such as diazoxide and cromakalim; it is inhibited by long-chain acyl-CoA esters and K[subscript ATP] channel inhibitors, such as glyburide and 5-hydroxydecanoate. We also demonstrated that the nucleotide regulatory sites on mitoK [subscript ATP] face the cytosol. Regulation of mitoK[subscript ATP] by long-chain acyl-CoA esters, together with matrix volume-dependent regulation of oxidative phosphorylation, Î²-oxidation of fatty acids, and the fact that mitoK[subscript ATP] regulates the matrix volume, suggests that mitoK[subscript ATP] has a role in regulation of oxidative phosphorylation and Î²-oxidation of fatty acids. Activation of cardiac mitoK [subscript ATP] by diazoxide and inhibition of this activation by 5- hydroxydecanoate, in addition to the cardioprotective effect of diazoxide, abolishing of this effect by 5-hydroxydecanoate, and the fact that both of these drugs are specific for regulation of mitoK [subscript ATP], but not the plasma membrane K [subscript ATP] channel, implies that mitoK [subscript ATP] has a role in cardioprotection against myocardial ischemia. The studies presented in this work suggest that mitoK [subscript ATP] is an important regulator of cellular bioenergetics. The opening of mitoK [subscript ATP] may be required to support cellular demands for increased work in heart, glucogenesis in liver, and thermogenesis in brown adipose tissue.
Yarov-Yarovoy, Vladimir, "Physiological and pharmacological properties of the ATP-sensitive potassium channel from the inner mitochondrial membrane" (1998). Scholar Archive. 114.