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SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans

Nature volume 430, pages 891896 (19 August 2004) | Download Citation

Subjects

Abstract

Muscular dystrophies are among the most common human genetic diseases and are characterized by progressive muscle degeneration. Muscular dystrophies result from genetic defects in components of the dystrophin–glycoprotein complex (DGC), a multimeric complex found in the muscle cell plasma membrane1. The DGC links the intracellular cytoskeleton to the extracellular matrix and is thought to be important for maintaining the mechanical integrity of muscles2 and organizing signalling molecules3. The exact role of the DGC in the pathogenesis of disease has, however, remained uncertain4. Mutations in Caenorhabditis elegans DGC genes lead to specific defects in coordinated movement and can also cause muscle degeneration5,6,7. Here we show that mutations in the gene snf-6 result in phenotypes indistinguishable from those of the DGC mutants, and that snf-6 encodes a novel acetylcholine/choline transporter. SNF-6 mediates the uptake of acetylcholine at neuromuscular junctions during periods of increased synaptic activity. SNF-6 also interacts with the DGC, and mutations in DGC genes cause a loss of SNF-6 at neuromuscular junctions. Improper clearing of acetylcholine and prolonged excitation of muscles might contribute to the pathogenesis of muscular dystrophies.

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Acknowledgements

We thank J. S. Kim, C. Yu and R. Ho for technical help, J. Rand and C. Bargmann for personal communication and helpful discussions, and all members of the McIntire laboratory for discussions and comments on the manuscript. Some strains were provided by the National Bioresource Project (Japan), the C. elegans Gene Knockout Consortium and the Caenorhabditis Genetics Center. This work was supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco, by a grant to S.L.M. from the Department of the Army, by a grant to J.E.R. from NIH and by a development grant to H.K. from the Muscular Dystrophy Association.

Author information

Affiliations

  1. Ernest Gallo Clinic and Research Center, Programs in Neuroscience and Biomedical Sciences, Department of Neurology, University of California at San Francisco, 5858 Horton Street, Suite 200, Emeryville, California 94608, USA

    • Hongkyun Kim
    • , Matthew J. Rogers
    •  & Steven L. McIntire
  2. Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois 60607, USA

    • Janet E. Richmond

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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Steven L. McIntire.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    Expression of STN-1 and SGN-1 in C. elegans muscle in the presence and absence of a snf-6 mutation

Word documents

  1. 1.

    Supplementary Figure Legend

  2. 2.

    Supplementary Methods

    Genetic Mapping, RNAi and Rescue.

  3. 3.

    Supplementary Table 1

    Characterization of the locomotory behaviour of mutants.

  4. 4.

    Supplementary Notes

    We did not observe any uptake of other compounds including a number of neurotransmitters.

Videos

  1. 1.

    Supplementary Video 1

    This movie was taken immediately after animals were transferred to a new plate. Wild-type N2 animals.

  2. 2.

    Supplementary Video 2

    This movie was taken immediately after animals were transferred to a new plate. dys-1 mutants.

  3. 3.

    Supplementary Video 3

    This movie was taken immediately after animals were transferred to a new plate. snf-6 mutants.

  4. 4.

    Supplementary Video 4

    This movie was taken immediately after animals were transferred to a new plate. snf-6; ace-1 mutants.

  5. 5.

    Supplementary Video 5

    Wild-type N2 movie before and after touch.

  6. 6.

    Supplementary Video 6

    snf-6 mutant movie before and after touch.

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DOI

https://doi.org/10.1038/nature02798

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