Abstract
Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation-contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca(2+) imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / metabolism
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Alleles
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Amino Acid Sequence
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Animals
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Base Sequence
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Central Nervous System / metabolism
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Central Nervous System / pathology
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Cleft Palate / genetics*
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Cleft Palate / physiopathology*
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Embryo, Nonmammalian / metabolism
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Excitation Contraction Coupling*
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Humans
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Malignant Hyperthermia / genetics*
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Malignant Hyperthermia / physiopathology*
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Molecular Sequence Data
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Mutation / genetics*
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Mutation, Missense / genetics
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Myofibrils / metabolism
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Myofibrils / ultrastructure
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Myotonia Congenita / genetics*
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Myotonia Congenita / pathology
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Myotonia Congenita / physiopathology*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Organ Specificity / genetics
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Phenotype
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Ryanodine Receptor Calcium Release Channel / metabolism
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Swimming
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Touch
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish Proteins / chemistry
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Zebrafish Proteins / genetics*
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Zebrafish Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Nerve Tissue Proteins
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RNA, Messenger
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Ryanodine Receptor Calcium Release Channel
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Stac3 protein, human
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Stac3 protein, zebrafish
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Zebrafish Proteins