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(Circulation Research. 2009;105:51.)
© 2009 American Heart Association, Inc.

Cellular Biology

Physical and Functional Interaction Between Calcineurin and the Cardiac L-Type Ca²⁺ Channel

Samvit Tandan, Yanggan Wang, Thomas T. Wang, Nan Jiang, Duane D. Hall, Johannes W. Hell, Xiang Luo, Beverly A. Rothermel, Joseph A. Hill

From the Departments of Internal Medicine (Cardiology) (S.T., Y.W., T.T.W., N.J., X.L., B.A.R., J.A.H.) and Molecular Biology (J.A.H.), University of Texas Southwestern Medical Center, Dallas; and Department of Pharmacology (D.D.H., J.W.H.), University of Iowa, Iowa City. Present address for Y.W.: Department of Pediatrics, Emory University, Atlanta, Ga.

Correspondence to Joseph A. Hill, MD, PhD, Division of Cardiology, UT Southwestern Medical Center, NB11.200, 5323 Harry Hines Blvd, Dallas, TX 75390-8573. E-mail joseph.hill{at}UTsouthwestern.edu

The L-type Ca²⁺ channel (LTCC) is the major mediator of Ca²⁺ influx in cardiomyocytes, leading to both mechanical contraction and activation of signaling cascades. Among these Ca²⁺-activated cascades is calcineurin, a protein phosphatase that promotes hypertrophic growth of the heart. Coimmunoprecipitations from heart extracts and pulldowns using heterologously expressed proteins provided evidence for direct binding of calcineurin at both the N and C termini of ₁1.2. At the C terminus, calcineurin bound specifically at amino acids 1943 to 1971, adjacent to a well-characterized protein kinase (PK)A/PKC/PKG phospho-acceptor site Ser1928. In vitro assays demonstrated that calcineurin can dephosphorylate ₁1.2. Channel function was increased in voltage-clamp recordings of I_Ca,L from cultured cardiomyocytes expressing constitutively active calcineurin, consistent with previous observations in cardiac hypertrophy in vivo. Conversely, acute suppression of calcineurin pharmacologically or with specific peptides decreased I_Ca,L. These data reveal direct physical interaction between the LTCC and calcineurin in heart. Furthermore, they demonstrate that calcineurin induces robust increases in I_Ca,L and highlight calcineurin as a key modulator of pathological electrical remodeling in cardiac hypertrophy.

Key Words: action potential remodeling • Ca²⁺ channels • calcineurin • electrophysiology • hypertrophy

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