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(Circulation Research. 2007;100:112.)
© 2007 American Heart Association, Inc.

Cellular Biology

Molecular Coupling of a Ca²⁺-Activated K⁺ Channel to L-Type Ca²⁺ Channels via -Actinin2

Ling Lu, Qian Zhang, Valeriy Timofeyev, Zhao Zhang, J. Nilas Young, Hee-Sup Shin, Anne A. Knowlton, Nipavan Chiamvimonvat

From the Division of Cardiovascular Medicine (L.L., Q.Z., V.T., Z.Z., A.A.K., N.C.), Department of Internal Medicine, University of California, Davis; Department of Veterans Affairs (A.A.K., N.C.), Northern California Health Care System, Mather; Department of Cardiothoracic Surgery (J.N.Y.), University of California, Davis; Jiangsu Key Lab for Bioresource Technology (L.L.), College of Life Science, Nanjing Normal University, China; Center for Calcium and Learning, Division of Life Sciences (H.-S.S.), Korea Institute of Science and Technology, Seoul, Republic of Korea.

Correspondence to Nipavan Chiamvimonvat, Division of Cardiovascular Medicine, University of California, Davis, One Shields Avenue, GBSF 6315, Davis, CA 95616. E-mail nchiamvimonvat{at}ucdavis.edu

Cytoskeletal proteins are known to sculpt the structural architecture of cells. However, their role as bridges linking the functional crosstalk of different ion channels is unknown. Here, we demonstrate that a small conductance Ca²⁺-activated K⁺ channels (SK2 channel), present in a variety of cells, where they integrate changes in intracellular Ca²⁺ concentration [Ca²⁺_i] with changes in K⁺ conductance and membrane potential, associate with L-type Ca²⁺ channels; Ca_v1.3 and Ca_v1.2 through a physical bridge, -actinin2 in cardiac myocytes. SK2 channels do not physically interact with L-type Ca²⁺ channels, instead, the 2 channels colocalize via their interaction with -actinin2 cytoskeletal protein. The association of SK2 channel with -actinin2 localizes the channel to the entry of external Ca²⁺ source, which regulate the channel function. Furthermore, we demonstrated that the functions of SK2 channels in atrial myocytes are critically dependent on the normal expression of Ca_v1.3 Ca²⁺ channels. Null deletion of Ca_v1.3 channel results in abnormal function of SK2 channel and prolongation of repolarization and atrial arrhythmias. Our study provides insight into the molecular mechanisms of the coupling of SK2 channel with voltage-gated Ca²⁺ channel, and represents the first report linking the coupling of 2 different types of ion channels via cytoskeletal proteins.

Key Words: K_Ca2.2 channel • SK2 channel • L-type Ca²⁺ channel • -actinin2

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