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(Circulation Research. 2005;97:1164.)
© 2005 American Heart Association, Inc.

Cellular Biology

Activation of the Endothelial Store-Operated I_SOC Ca²⁺ Channel Requires Interaction of Protein 4.1 With TRPC4

Donna L. Cioffi, Songwei Wu, Mikhail Alexeyev, Steven R. Goodman, Michael X. Zhu, Troy Stevens

From the Center for Lung Biology (D.L.C., S.W., M.A., T.S.), Department of Pharmacology (D.L.C., S.W., T.S.), and Department of Cell Biology and Neuroscience (M.A.), the University of South Alabama College of Medicine, Mobile; Department of Molecular and Cell Biology (S.R.G.), the University of Texas at Dallas; and Department of Neuroscience and Center for Molecular Neurobiology (M.X.Z.), the Ohio State University, Columbus.

Correspondence to Troy Stevens, PhD, Professor, Center for Lung Biology, Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL 36688. E-mail tstevens{at}jaguar1.usouthal.edu

Store-operated calcium (SOC) entry represents the principal Ca²⁺ entry pathway into nonexcitable cells. Despite intensive investigation, mechanisms underlying activation of SOC entry have remained elusive. The endothelial I_SOC channel is a Ca²⁺-selective SOC entry channel to which the transient receptor potential (TRP) proteins TRPC1 and TRPC4 contribute subunits. Activation of I_SOC is specifically regulated by the spectrin–actin membrane skeleton; however, the nature of coupling between the I_SOC channel and membrane skeleton is unknown. Here we demonstrate that protein 4.1 is an essential component of the I_SOC channel gating mechanism. Protein 4.1 interacts with TRPC4 and the membrane skeleton. Deletion of the protein 4.1 binding domain on TRPC4 or peptide competition to the protein 4.1 binding domain prevents I_SOC activation. These findings reveal that interaction of protein 4.1 with TRPC4 is required for activation of the endothelial I_SOC channel.

Key Words: cytoskeleton • I_SOC • spectrin • store-operated Ca²⁺ • entry • TRPC

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