Intracellular ATP binding is required to activate the slowly activating K+ channel IKs.

TitleIntracellular ATP binding is required to activate the slowly activating K+ channel IKs.
Publication TypeJournal Article
Year of Publication2013
AuthorsLi Y, Gao J, Lu Z, McFarland K, Shi J, Bock K, Cohen IS, Cui J
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue47
Pagination18922-7
Date Published2013 Nov 19
Abstract

Gating of ion channels by ligands is fundamental to cellular function, and ATP serves as both an energy source and a signaling molecule that modulates ion channel and transporter functions. The slowly activating K(+) channel IKs in cardiac myocytes is formed by KCNQ1 and KCNE1 subunits that conduct K(+) to repolarize the action potential. Here we show that intracellular ATP activates heterologously coexpressed KCNQ1 and KCNE1 as well as IKs in cardiac myocytes by directly binding to the C terminus of KCNQ1 to allow the pore to open. The channel is most sensitive to ATP near its physiological concentration, and lowering ATP concentration in cardiac myocytes results in IKs reduction and action potential prolongation. Multiple mutations that suppress IKs by decreasing the ATP sensitivity of the channel are associated with the long QT (interval between the Q and T waves in electrocardiogram) syndrome that predisposes afflicted individuals to cardiac arrhythmia and sudden death. A cluster of basic and aromatic residues that may form a unique ATP binding site are identified; ATP activation of the wild-type channel and the effects of the mutations on ATP sensitivity are consistent with an allosteric mechanism. These results demonstrate the activation of an ion channel by intracellular ATP binding, and ATP-dependent gating allows IKs to couple myocyte energy state to its electrophysiology in physiologic and pathologic conditions.

DOI10.1155/2013/734893
Alternate JournalProc. Natl. Acad. Sci. U.S.A.