Stac3 is a Component of the Excitation-Contraction Coupling Machinery and is Mutated in Native American Myopathy.

[摘要] Excitation-contraction (EC) coupling is the mechanism by which muscle translates depolarization of the sarcolemma into Ca2+ release from the sarcoplasmic reticulum (SR) required for muscle contraction.EC coupling occurs at the junctions of transverse (t) tubules and SR called triads and is dependent on interactions between the dihydropyridine receptor (DHPR) in t-tubules that is the voltage detector, and the ryanodine receptor (RyR1) in the SR that is the Ca2+ release channel. Despite the well-studied role in EC coupling of DHPR and RyR1, other components of the molecular complex are less understood. A mutagenesis screen of zebrafish identified an autosomal, recessive mutation that causes poor mobility and reduced Ca2+ release in skeletal muscle, yet exhibits normal output from the central nervous system to muscles. Through meiotic mapping, a null mutation in stac3, a skeletal muscle-specific gene encoding a putative adaptor protein, was identified. As stac3 mutants display myopathic features, we explored whether stac3 mutations might cause human myopathies and found that a mutation in STAC3 is the basis of Native American Myopathy, which is characterized by muscle weakness and susceptibility to malignant hyperthermia. The Stac3 protein was further characterized and found to directly interact with the EC coupling complex, and to function in normal trafficking and arrangement of the DHPR in arrays of four called tetrads that are essential for Ca2+ release. The neuronally expressed Stac1 protein is a homolog of Stac3, but its function is unknown. Informed by our research on Stac3 in skeletal muscle, we probed the function of Stac1 in neurons. We find stac1 is expressed in a subset of spinal cord neurons in zebrafish embryos called Kolmer-Agdur (KA) interneurons that are likely involved in the neuronal circuit that generates swim behaviors. To determine the function of Stac1, we knocked down expression of Stac1 protein with an antisense morpholino oligonucleotide (MO), which resulted in a motility defect in embryos, indicating KA interneurons are involved in the neuronal circuit underlying swim behavior, and Stac1 is required swimming. These results indicate that members of the previously uncharacterized stac family of genes are important in normal muscle and neuronal physiology.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Cellular and Molecular Physiology of Skeletal Muscle and Neurons;Molecular;Cellular and Developmental Biology;Science;Cellular & Molecular Biology