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PNAS 101 (25): 9387-9392

Copyright © 2004 by the National Academy of Sciences.

Medical Sciences

TRPC3 channels confer cellular memory of recent neuromuscular activity

Paul Rosenberg *, April Hawkins *, Jonathan Stiber *, John M. Shelton {dagger}, Kelley Hutcheson *, Rhonda Bassel-Duby {dagger}, Dong Min Shin {ddagger}, Zhen Yan *, and R. Sanders Williams *, §

*Departments of Internal Medicine and Pharmacology, Duke University Medical School, Durham, NC 27710; {dagger}Department of Molecular Biology and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; and {ddagger}Department of Oral Biology, Yonsei University, Seoul 120-749, South Korea

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA

Accepted for publication May 11, 2004.

Received for publication December 9, 2003.

Abstract: Skeletal muscle adapts to different patterns of motor nerve activity by alterations in gene expression that match specialized properties of contraction, metabolism, and muscle mass to changing work demands (muscle plasticity). Calcineurin, a calcium/calmodulin-dependent, serine–threonine protein phosphatase, has been shown to control programs of gene expression in skeletal muscles, as in other cell types, through the transcription factor nuclear factor of activated T cells (NFAT). This study provides evidence that the function of NFAT as a transcriptional activator is regulated by neuromuscular stimulation in muscles of intact animals and that calcium influx from the transient receptor potential (TRPC3) channel is an important determinant of NFAT activity. Expression of TRPC3 channels in skeletal myocytes is up-regulated by neuromuscular activity in a calcineurin-dependent manner. These data suggest a mechanism for cellular memory in skeletal muscles whereby repeated bouts of contractile activity drive progressively greater remodeling events.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: NFAT, nuclear factor of activated T cells; RYR, ryanodine receptor; CPA, cyclopiazoic acid; EDL, extensor digitorum longus.

§ To whom correspondence should be addressed at: Duke University Medical Center, Box 2927, Durham, NC 27710. E-mail: rosen029{at}

© 2004 by The National Academy of Sciences of the USA

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