K. D. Garlid, P. Paucek, V. Yarov-Yarovoy, X. Sun, and P. A. Schindler
(1996) The mitochondrial KATP channel as a receptor for potassium channel
openers. J. Biol. Chem. 271, 8796-8799.
Abstract:
The biochemical properties of the mitochondrial KATP channel are very similar
to those of plasma membrane KATP 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 KATP channels are highly sensitive to the family of drugs
known as K+ channel openers, raising the question whether mitochondrial KATP
channels are similarly sensitive to these agents. We addressed this question
by measuring K+ flux in intact rat liver mitochondria and in liposomes containing
KATP 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 (K1/2 = 0.4 microM),
cromakalim (K1/2 = 1 microM), and two developmental cromakalim analogues,
EMD60480 and EMD57970 (K1/2 = 6 nM). Similar K1/2 values were observed in
intact mitochondria. These potencies are well within the range observed with
plasma membrane KATP channels. We also compared the potencies of these K+
channel openers on the plasma membrane KATP channel purified from beef heart
myocytes. The KATP 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. We suggest that the
mitochondrial KATP channel is an important intracellular receptor that should
be taken into account in considering the pharmacology of K+ channel openers.
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