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Modulation of ATP-sensitive K+ channels in skeletal muscle by intracellular protons


SINCE their discovery in cardiac muscle1, ATP-sensitive K+(KATP) channels have been identified in pancreatic β-cells2, skeletal muscle3, smooth muscle4and central neurons5. The activity of KATP channels is inhibited by the presence of cytosolic ATP. Their wide distribution indicates that they could have important physiological roles that may vary between tissues. In muscle cells the role of K+ channels is to control membrane excitability and the duration of the action potential. In anoxic cardiac ventricular muscle KATPchannels are believed to be responsible for shortening the action potential6, and it has been proposed that a fall in ATP concentration during metabolic exhaustion increases the activity of KATP channels in skeletal muscle7, which may reduce excitability. But the intracellular concentration of ATP in muscle is buffered by creatine phosphate to 5–10 mM, and changes little, even during sustained activity8. This concentration is much higher than the intracellular ATP concentration required to half block the KATP-channel current in either cardiac muscle (0.1 mM)1 or skeletal muscle (0.14 mM)9, indicating that the open-state probability of KATP channels is normally very low in intact muscle. So it is likely that some additional means of regulating the activity of KATP channels exists, such as the binding of nucleotides other than ATP10–12. Here I present evidence that a decrease in intracellular pH (pHi) markedly reduces the inhibitory effect of ATP on these channels in excised patches from frog skeletal muscle. Because sustained muscular activity can decrease pHi by almost 1 unit13,14 in the range at which KATP channels are most sensitive to pHi it is likely that the activity of these channels in skeletal muscle is regulated by intracellular protons under physiological conditions.

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Davies, N. Modulation of ATP-sensitive K+ channels in skeletal muscle by intracellular protons. Nature 343, 375–377 (1990).

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