Inhibition of the mitochondrial KATP channel by long-chain
acyl-CoA esters and activation by guanine nucleotides.
P. Paucek, V. Yarov-Yarovoy, X. Sun, and K. D. Garlid (1996) Inhibition
of the mitochondrial KATP channel by long-chain acyl-CoA esters and activation
by guanine nucleotides. J. Biol. Chem. 271, 32084-32088.
Abstract:
The mitochondrial KATP channel (mitoKATP) is highly sensitive
to ATP, which inhibits K+ flux with K1/2 values of 20-40 microM. This raises
the question, how can mitoKATP be opened in the presence of physiological
concentrations of ATP? We measured K+ flux in liposomes reconstituted with
purified mitoKATP and found that guanine nucleotides are potent activators
of this channel. ATP-inhibited K+ flux was completely reactivated by both
GTP (K1/2 = 7 microM) and GDP (K1/2 = 140 microM). These ligands had no effect
in the absence of ATP. The K1/2 for ATP inhibition exhibited quadratic dependence
on [GTP] and [GDP], consistent with two binding sites for guanine nucleotides.
We also found that palmitoyl-CoA and oleoyl-CoA inhibited K+ flux through
reconstituted mitoKATP with K1/2 values of 260 nM and 80 nM, respectively.
This inhibition was reversed by GTP (K1/2 = 232 microM) as well as by the
K+ channel openers cromakalim (20 microM) and diazoxide (10 microM). Inhibition
of mitoKATP by long-chain acyl-CoA esters, like that of ATP, exhibited an
absolute requirement for Mg2+ ions. We propose that the open-closed state
of the mitochondrial KATP channel is determined by the relative cytosolic
concentrations of GTP and long-chain acyl-CoA esters.