Abstract

The hypothesis is that cardiac sarcoplasmic reticulum (SR) is subspecialized. The goal of the proposed research is to document this with an in vitro biochemical approach. A heterogeneous cardiac SR preparation will be centrifuged into subpopulations of ryanodine dine-sensitive (RS) and ryanodine-insensitive (RI) SR vesicles, and the different functional, compositional, and morphological properties of the two subpopulations of SR vesicles determined. Functional studies will address Ca2 plus metabolism. Preliminary data indicate that RI vesicles have a high Ca2 plus pump density and a high capacity for Ca2 plus uptake. Ca2 plus uptake by RS vesicles is selectively stimulated by the drug, ryanodine, which may block distinct Ca2 plus efflux channels present only in these vesicles. Compositional studies will characterize unique proteins in either subpopulation of vesicles which are responsible for their different Ca2 plus handling properties, and morphological studies will determine the subcellular localization of the two types o SR in intact meocardium. Although others have isolated functionally different subpopulations of SR from skeletal muscle, this study is the first to attempt this with cardiac preparations. This study will further clarify the role of SR in regulating excitation-contraction coupling in mammalian myocardium.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL028556-03
Application #
3339923
Study Section
Physiology Study Section (PHY)
Project Start
1983-01-01
Project End
1986-12-31
Budget Start
1985-01-01
Budget End
1985-12-31
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202

  Publications

Chopra, Nagesh; Kannankeril, Prince J; Yang, Tao et al. (2007) Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice. Circ Res 101:617-26
Knollmann, Bjorn C; Chopra, Nagesh; Hlaing, Thinn et al. (2006) Casq2 deletion causes sarcoplasmic reticulum volume increase, premature Ca2+ release, and catecholaminergic polymorphic ventricular tachycardia. J Clin Invest 116:2510-20
Kirchhefer, Uwe; Hanske, Gabriela; Jones, Larry R et al. (2006) Overexpression of junctin causes adaptive changes in cardiac myocyte Ca(2+) signaling. Cell Calcium 39:131-42
Kirchhefer, Uwe; Baba, Hideo A; Hanske, Gabriela et al. (2004) Age-dependent biochemical and contractile properties in atrium of transgenic mice overexpressing junctin. Am J Physiol Heart Circ Physiol 287:H2216-25
Gyorke, Inna; Hester, Nichole; Jones, Larry R et al. (2004) The role of calsequestrin, triadin, and junctin in conferring cardiac ryanodine receptor responsiveness to luminal calcium. Biophys J 86:2121-8
Kirchhefer, Uwe; Jones, Larry R; Begrow, Frank et al. (2004) Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to beta-adrenergic agonists. Cardiovasc Res 62:122-34
Yang, Alexander; Sonin, Dimitry; Jones, Larry et al. (2004) A beneficial role of cardiac P2X4 receptors in heart failure: rescue of the calsequestrin overexpression model of cardiomyopathy. Am J Physiol Heart Circ Physiol 287:H1096-103
Tijskens, Pierre; Jones, Larry R; Franzini-Armstrong, Clara (2003) Junctin and calsequestrin overexpression in cardiac muscle: the role of junctin and the synthetic and delivery pathways for the two proteins. J Mol Cell Cardiol 35:961-74
Kirchhefer, Uwe; Neumann, Joachim; Bers, Donald M et al. (2003) Impaired relaxation in transgenic mice overexpressing junctin. Cardiovasc Res 59:369-79
Kirchhefer, Uwe; Baba, Hideo A; Kobayashi, Yvonne M et al. (2002) Altered function in atrium of transgenic mice overexpressing triadin 1. Am J Physiol Heart Circ Physiol 283:H1334-43

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