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Biophys J, May 1998, p. 2335-2351, Vol. 74, No. 5

ATP Inhibition and Rectification of a Ca2+-Activated Anion Channel in Sarcoplasmic Reticulum of Skeletal Muscle

Gerard P. Ahern and Derek R. Laver

John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia

We describe ATP-dependent inhibition of the 75-105-pS (in 250 mM Cl-) anion channel (SCl) from the sarcoplasmic reticulum (SR) of rabbit skeletal muscle. In addition to activation by Ca2+ and voltage, inhibition by ATP provides a further mechanism for regulating SCl channel activity in vivo. Inhibition by the nonhydrolyzable ATP analog 5'-adenylylimidodiphosphate (AMP-PNP) ruled out a phosphorylation mechanism. Cytoplasmic ATP (~1 mM) inhibited only when Cl- flowed from cytoplasm to lumen, regardless of membrane voltage. Flux in the opposite direction was not inhibited by 9 mM ATP. Thus ATP causes true, current rectification in SCl channels. Inhibition by cytoplasmic ATP was also voltage dependent, having a KI of 0.4-1 mM at -40 mV (Hill coefficient ~2), which increased at more negative potentials. Luminal ATP inhibited with a KI of ~2 mM at +40 mV, and showed no block at negative voltages. Hidden Markov model analysis revealed that ATP inhibition 1) reduced mean open times without altering the maximum channel amplitude, 2) was mediated by a novel, single, voltage-independent closed state (~1 ms), and 3) was much less potent on lower conductance substates than the higher conductance states. Therefore, the SCl channel is unlikely to pass Cl- from cytoplasm to SR lumen in vivo, and balance electrogenic Ca2+ uptake as previously suggested. Possible roles for the SCl channel in the transport of other anions are discussed.

Biophys J, May 1998, p. 2335-2351, Vol. 74, No. 5
© 1998 by the Biophysical Society   0006-3495/98/05/2335/17  $2.00


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