Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 923K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JGP Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lueck, J. D. Articles by Dirksen, R. T. Search for Related Content PubMed PubMed Citation Articles by Lueck, J. D. Articles by Dirksen, R. T. Social Bookmarking                            What's this?

¹ Department of Physiology and Pharmacology, University of Rochester, Rochester, NY 14642
² Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642
³ Department of Molecular Genetics and Microbiology and the Genetic Institute, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32610

Correspondence to Robert T. Dirksen: Robert_Dirksen{at}URMC.Rochester.edu

Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)₂₅₀ repeats (HSA^LR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1–3-wk-old wild-type and HSA^LR mice. The results indicate that peak ClC-1 current density at –140 mV is reduced >70% (–48.5 ± 3.6 and –14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18–20- d-old HSA^LR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSA^LR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSA^LR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1^E3/E3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat–containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				T. H. Pedersen, F. V. de Paoli, J. A. Flatman, and O. B. Nielsen Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers J. Gen. Physiol., October 1, 2009; 134(4): 309 - 322. [Abstract] [Full Text] [PDF]

				T. H. Pedersen, W. A. Macdonald, F. V. de Paoli, I. S. Gurung, and O. B. Nielsen Comparison of regulated passive membrane conductance in action potential-firing fast- and slow-twitch muscle J. Gen. Physiol., October 1, 2009; 134(4): 323 - 337. [Abstract] [Full Text] [PDF]

				Y. Kino, C. Washizu, Y. Oma, H. Onishi, Y. Nezu, N. Sasagawa, N. Nukina, and S. Ishiura MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1 Nucleic Acids Res., October 1, 2009; 37(19): 6477 - 6490. [Abstract] [Full Text] [PDF]

				T. M. Wheeler, K. Sobczak, J. D. Lueck, R. J. Osborne, X. Lin, R. T. Dirksen, and C. A. Thornton Reversal of RNA Dominance by Displacement of Protein Sequestered on Triplet Repeat RNA Science, July 17, 2009; 325(5938): 336 - 339. [Abstract] [Full Text] [PDF]

				R. J. Osborne, X. Lin, S. Welle, K. Sobczak, J. R. O'Rourke, M. S. Swanson, and C. A. Thornton Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy Hum. Mol. Genet., April 15, 2009; 18(8): 1471 - 1481. [Abstract] [Full Text] [PDF]

				S. Boncompagni, A. E. Rossi, M. Micaroni, G. V. Beznoussenko, R. S. Polishchuk, R. T. Dirksen, and F. Protasi Mitochondria Are Linked to Calcium Stores in Striated Muscle by Developmentally Regulated Tethering Structures Mol. Biol. Cell, February 1, 2009; 20(3): 1058 - 1067. [Abstract] [Full Text] [PDF]

				G. Zifarelli and M. Pusch The Muscle Chloride Channel ClC-1 Is Not Directly Regulated by Intracellular ATP J. Gen. Physiol., February 1, 2008; 131(2): 109 - 116. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents