title: Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.
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.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Horstick
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Linsley
authors.forename: James J
authors.initials: JJ
authors.lastname: Dowling
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: Kristin K
authors.initials: KK
authors.lastname: McDonald
authors.forename: Allison
authors.initials: A
authors.lastname: Ashley-Koch
authors.forename: Louis
authors.initials: L
authors.lastname: Saint-Amant
authors.forename: Akhila
authors.initials: A
authors.lastname: Satish
authors.forename: Wilson W
authors.initials: WW
authors.lastname: Cui
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Sprague
authors.forename: Demetra S
authors.initials: DS
authors.lastname: Stamm
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Powell
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
authors.forename: Clara
authors.initials: C
authors.lastname: Franzini-Armstrong
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hirata
authors.forename: John Y
authors.initials: JY
authors.lastname: Kuwada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000503:physiopathology*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D056966:Excitation Contraction Coupling; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000503:physiopathology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009210:Myofibrils / Q000378:metabolism / Q000648:ultrastructure; D009224:Myotonia Congenita / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D013550:Swimming; D014110:Touch; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; C585275:Stac3 protein, human; C585276:Stac3 protein, zebrafish; D029961:Zebrafish Proteins