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(Circulation Research. 2009;105:7.)
© 2009 American Heart Association, Inc.

Editorials

Calcineurin Finds a New Partner in the L-Type Ca²⁺ Channel

Geoffrey S. Pitt

From the Ion Channel Research Unit, Department of Medicine, Duke University Medical Center, Durham, NC.

Correspondence to Geoffrey S. Pitt, Department of Medicine, Duke University Medical Center, Box 103030 Medical Center, Durham, NC 27710. E-mail geoffrey.pitt@duke.edu

See related articles, pages 51–60

Key Words: calcineurin • L-type Ca²⁺ channel • hypertrophy • phosphatase

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Calcineurin is a Ca²⁺/calmodulin-sensitive phosphatase that sits near the top of signaling pathways leading to pathological cardiac hypertrophy.¹ Pathological stressors activate calcineurin, for which nuclear factor of activated T cells (NFAT) is a principal substrate. Dephosphorylation unmasks a nuclear localization signal on NFAT, which then translocates to the nucleus and, there, serves as part of a transcription factor complex able to initiate gene expression cascades that induce cardiac hypertrophy and subsequent heart failure. Determining how calcineurin is specifically activated in response to hypertrophic stressors by the same Ca²⁺ signal used for excitation–contraction coupling has been a major challenge. Triggered by Ca²⁺ influx through Ca_V1.2 voltage-gated Ca²⁺ channels at the sarcolemmal membrane, intracellular calcium briefly increases 10-fold with each heart beat to generate myocyte contraction. Almost as quickly, intracellular calcium falls to its baseline level, allowing myocyte relaxation and preparation for the next beat.

There are 2 leading proposals for how Ca²⁺ could activate the calcineurin/NFAT pathway or function as a versatile regulator of multiple other signaling cascades in the face of the large Ca²⁺ oscillations driving each cycle of contraction and relaxation. One is that modulation of the amplitude and/or frequency of the oscillatory contractile Ca²⁺ signal triggers particular Ca²⁺ sensors that then activate particular downstream signaling pathways, such as calcineurin activation.² The alternative suggests that local Ca²⁺ signaling microdomains, secluded from the contractile oscillations, feed into specific signaling cascades, such as calcineurin activation.^3,4 In this issue of Circulation Research, Tandan et al⁵ propose that calcineurin binds . . . [Full Text of this Article]

Related Article:

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, and Joseph A. Hill
Circ. Res. 2009 105: 51-60. [Abstract] [Full Text] [PDF]