Abstract

description): The overall goal of this proposal is to elucidate the basis for structural organization of the calcium release units (CRUs) of cardiac and skeletal muscle which underlie excitation-contraction coupling. CRUs are comprised of junctional sarcoplasmic reticulum (jSR) which are composed of a luminal calcium-binding protein, calsequestrin (CSQ), and several membrane proteins which include the calcium-release channel (ryanodine receptor; RyRs), and supporting proteins junctin and triadin. The adjacent areas of sarcolemma include L-type calcium channels (dihydropyridine receptors; DHPRs). To determine the basis for the assembly, organization, and maintenance of structural integrity of these units, structure will be assessed by electron microscopy, using thin sections and freeze fracture methods, and protein composition will be assessed using immunofluorescence coupled to confocal microscopy and by Western blotting. Three strategies will be used to assess the effect of altered protein composition on the structure of CRUs. 1) Transgenic mice which overexpress one or more of the CRU proteins will be studied. 2) Muscle specific CRU proteins will be expressed in non-muscle cells in order to determine the proteins necessary for formation of CRUs. 3) The composition of CRUs in skeletal muscle of Amphioxus will be examined using molecular biology and ultrastructural approaches.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL048093-06
Application #
2910549
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Lymn, Richard W
Project Start
1993-07-01
Project End
2003-06-30
Budget Start
1999-07-15
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Lavorato, Manuela; Huang, Tai-Qin; Iyer, Venkat Ramesh et al. (2015) Dyad content is reduced in cardiac myocytes of mice with impaired calmodulin regulation of RyR2. J Muscle Res Cell Motil 36:205-14
Perni, Stefano; Dynes, Joseph L; Yeromin, Andriy V et al. (2015) Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proc Natl Acad Sci U S A 112:E5533-42
Perni, Stefano; Marsden, Kurt C; Escobar, Matias et al. (2015) Structural and functional properties of ryanodine receptor type 3 in zebrafish tail muscle. J Gen Physiol 145:173-84
Guo, Ang; Zhang, Xiaoying; Iyer, Venkat Ramesh et al. (2014) Overexpression of junctophilin-2 does not enhance baseline function but attenuates heart failure development after cardiac stress. Proc Natl Acad Sci U S A 111:12240-5
Franzini-Armstrong, Clara (2014) Memories of Annemarie Weber. Anat Rec (Hoboken) 297:1543-7
Eltit, Jose M; Franzini-Armstrong, Clara; Perez, Claudio F (2014) Amino acid residues 489-503 of dihydropyridine receptor (DHPR) ?1a subunit are critical for structural communication between the skeletal muscle DHPR complex and type 1 ryanodine receptor. J Biol Chem 289:36116-24
Dayal, Anamika; Bhat, Vinayakumar; Franzini-Armstrong, Clara et al. (2013) Domain cooperativity in the ?1a subunit is essential for dihydropyridine receptor voltage sensing in skeletal muscle. Proc Natl Acad Sci U S A 110:7488-93
Horstick, Eric J; Linsley, Jeremy W; Dowling, James J et al. (2013) Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun 4:1952
Park, Chang Sik; Chen, Shan; Lee, Hoyong et al. (2013) Targeted ablation of the histidine-rich Ca(2+)-binding protein (HRC) gene is associated with abnormal SR Ca(2+)-cycling and severe pathology under pressure-overload stress. Basic Res Cardiol 108:344
Huang, Xiaohu; Sun, Lei; Ji, Shuangxi et al. (2013) Kissing and nanotunneling mediate intermitochondrial communication in the heart. Proc Natl Acad Sci U S A 110:2846-51

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