Browsing by Subject "Sarcoplasmic Reticulum Calcium-Transporting ATPases"
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Item Discovery and Characterization of Genes Involved in Muscle Calcium Handling(2015-08-10) Nelson, Benjamin Rhett; Wilkie, Thomas; Olson, Eric N.; Mendell, Joshua T.; Stull, JamesMuscle tissue requires continuous cycling of calcium release and clearance to generate and sustain contraction. When the plasma membrane of a muscle fiber becomes electrically excited, a voltage sensor in the membrane, called the dihydropyridine receptor (DHPR), becomes activated and signals to the calcium release channel located in the membrane of the sarcoplasmic reticulum (SR), called the ryanodine receptor (RyR). When the RyR channel is activated, calcium is released into the cytoplasm from the SR, the primary calcium storage compartment of muscle fibers. Calcium then binds to the sarcomere, activating the motor activity of the myosin filaments, and causes the fiber to contract. Following contraction, most of the cytosolic and sarcomeric calcium is recycled back to the SR by the sarco/endoplasmic reticulum ATPase (SERCA). Although most components of the calcium handling pathway are thought to be already known, the large number muscle-specific genes with unknown functions would suggest that additional components may yet be undiscovered. The first goal of this study was to carry out initial functional characterization of the Stac3 knockout mouse, in which muscle contraction is severely defective. We found that mice lacking Stac3, a gene with skeletal muscle-specific expression, lack muscle contraction because of a defect in excitation-contraction coupling, that is the link between membrane excitation and SR calcium release. The second goal was to identify small peptides that may play a role in muscle function. We examined codon conservation in transcripts annotated as long non-coding RNAs and discovered a transcript that encodes a 34-amino-acid transmembrane peptide with cardiac and slow-twitch muscle expression that we have named Dwarf Open Reading Frame or DWORF. Overexpression of this peptide in cardiac myocytes increases the peak calcium release during contraction while also increasing the rate of calcium clearance. We conclude that DWORF likely serves to increase the apparent enzymatic activity of SERCA. Together the discoveries of Stac3 and Dworf suggest that many important genes in muscle function may be awaiting a closer look or have not yet been discovered at all.Item Herp Reduces ER Calcium Content by Proteasomal Degradation of SERCA(2007-08-08) Mao, Yuntao Steve; Kodadek, Thomas J.Herp, an endoplasmic reticulum (ER) stress inducible protein, reduces ER Ca2+ content in neurons and prevents their apoptosis. An understanding of the mechanism by which Herp decreases ER Ca2+ content requires studies of Herp interacting proteins, which could be SERCA and the proteasome. Herp may recruit the proteasome from the cytosol to the ER membrane, thereby facilitating the ER associated degradation (ERAD) of SERCA. The proteasome recruitment and the subsequent degradation of SERCA reduce ER lumenal Ca2+ concentration and the Ca2+ release during ER stress which counteracts the activation of apoptosis. This proposal describes how to determine the mechanism through which Herp reduces ER Ca2+ content, how to test the proteasomal degradation of SERCA, how to illustrate the proteasome recruitment to the ER membrane, and how to demonstrate the interaction between Herp and SERCA. The work will provide a new regulatory link between ER stress and Ca2+ homeostasis. In addition, studies of the proteasomal degradation of SERCA will broaden our present understanding of the regulation of SERCA. Since dysregulation of Ca2+ homeostasis has been implicated in the pathophysiology of several neurodegenerative diseases like Alzheimer's and Huntington's, research focused on Herp may lead to insights regarding therapies for those.