title: Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3.
abstract: Skeletal muscle contractions are initiated by an increase in Ca2+released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAMmyofibers exhibited increased caffeine-induced Ca2+release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+in internal stores, which is consistent with increased SR luminal Ca2+These findings define critical roles for Stac3 in EC coupling and human disease.
authors.affiliation: Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109.|Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Linsley
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: I-Uen
authors.initials: IU
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Linda
authors.initials: L
authors.lastname: Groom
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642.
authors.forename: Viktor
authors.initials: V
authors.lastname: Yarotskyy
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lavorato
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.|Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Horstick
authors.affiliation: Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02912.
authors.forename: Drew
authors.initials: D
authors.lastname: Linsley
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; armstroc@mail.med.upenn.edu robert_dirksen@urmc.rochester.edu kuwada@umich.edu.
authors.forename: Clara
authors.initials: C
authors.lastname: Franzini-Armstrong
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642; armstroc@mail.med.upenn.edu robert_dirksen@urmc.rochester.edu kuwada@umich.edu.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.affiliation: Cell and Molecular Biology Program, University of Michigan, Ann Arbor, MI 48109; armstroc@mail.med.upenn.edu robert_dirksen@urmc.rochester.edu kuwada@umich.edu.|Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: John Y
authors.initials: JY
authors.lastname: Kuwada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium; D020746:Calcium Channels, L-Type / Q000502:physiology*; D004625:Embryo, Nonmammalian; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D009224:Myotonia Congenita; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; C585276:Stac3 protein, zebrafish; D029961:Zebrafish Proteins; D002110:Caffeine; D002118:Calcium
keywords: Native American myopathy; dihydropyridine receptor; excitation–contraction coupling; skeletal muscle; zebrafish