The mitochondrial K-ATP channel as a receptor for potassium channel openers

The biochemical properties of the mitochondrial K-ATP channel are very similar to those of plasma membrane K-ATP channels, including inhibition by low concentrations of ATP and glyburide (Paucek, P,, Mironova, G., Mahdi, F., Beavis, A, D,, Woldegiorgis, G,, and Garlid, K. D, (1992) J, Biol, Chem. 267, 26062-26069), Plasma membrane K-ATP channels are highly sensitive to the family of drugs known as K+ channel openers, raising the question whether mitochondrial K-ATP channels are similarly sensitive to these agents, Ne addressed this question by measuring K+ flux in intact rat liver mitochondria and in liposomes containing K-ATP channels purified from rat liver and beef heart mitochondria, K+ channel openers completely reversed ATP inhibition of K+ flux in both systems, In Liposomes, ATP-inhibited K+ flux was restored by diazoxide (K-1/2 = 0.4 mu M), cromakalim (K-1/2 = 1 mu M), and two developmental cromakalim analogues, EMD60480 and EMD57970 (K-1/2 = 6 nM), Similar K-1/2 values were observed in intact mitochondria, These potencies are well within the range observed with plasma membrane K-ATP channels, We also compared the potencies of these K+ channel openers on the plasma membrane K-ATP channel purified from beef heart myocytes, The K-ATP channel from cardiac mitochondria is 2000-fold more sensitive to diazoxide than the channel from cardiac sarcolemma, indicating that two distinct receptor subtypes coexist within the myocyte. Ne suggest that the mitochondrial K-ATP channel is an important intracellular receptor that should be taken into account in considering the pharmacology of K+ channel openers.