The overall goal of this Program Project is to generate basic knowledge concerning fundamental cellular mechanisms that mediate the normal intracellular environment essential for coordinated electrical and contractile function in heart and blood vessels. A unifying subtheme selected for this competitive renewal is Ca2+ ions and protein phosphorylation - interacting subcellular mechanisms of regulation in cardiac and vascular muscle. The broad specific aims that will be pursued through interactive and collaborative studies are: 1) to delineate key molecular mechanisms that account for the unique roles of the cholinergic and adrenergic limbs of the autonomic nervous system in regulating electrical and/or contractile function of cardiac and vascular muscle, 2) to identify and characterize pivotal protein kinase and/or phosphatase systems that commonly affect muscle electrophysiology or contractility through direct action on ion pumps, antiporters, channels or contractile and regulatory proteins, 3) to isolate and define the interaction of contractile and regulatory protein complexes that account for the unique force maintenance mechanism in vascular smooth muscle, a process that is dependent upon both Ca2+ and protein phosphorylation, and 4) to study specific ion channels, antiporters, or pump systems at the cellular and membrane level, elucidate specific molecular mechanisms of regulation and investigate interactions of these mechanisms at the intact tissue level. A variety of preparations or methodologies will be utilized in order to pursue the specific aims including cellular microelectrodes, perfused hearts, isolated cardiac myocytes, cultured cells, planar lipid bilayers, protein purification, monoclonal antibodies, protein sequencing, muscle mechanics, and recombinant DNA. This Program Project will produce a body of information that can serve as a logical paradigm for subsequent study of disease states such as cardiac arrhythmia and atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL006308-29
Application #
3097390
Study Section
(SRC)
Project Start
1978-03-01
Project End
1993-02-28
Budget Start
1989-03-01
Budget End
1990-02-28
Support Year
29
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Fukunaga, K; Muller, D; Ohmitsu, M et al. (2000) Decreased protein phosphatase 2A activity in hippocampal long-term potentiation. J Neurochem 74:807-17
Neumann, J; Boknik, P; DePaoli-Roach, A A et al. (1998) Targeted overexpression of phospholamban to mouse atrium depresses Ca2+ transport and contractility. J Mol Cell Cardiol 30:1991-2002
Zhao, Y; Boguslawski, G; Zitomer, R S et al. (1997) Saccharomyces cerevisiae homologs of mammalian B and B' subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions. J Biol Chem 272:8256-62
Csortos, C; Zolnierowicz, S; Bako, E et al. (1996) High complexity in the expression of the B' subunit of protein phosphatase 2A0. Evidence for the existence of at least seven novel isoforms. J Biol Chem 271:2578-88
Altschuld, R A; Starling, R C; Hamlin, R L et al. (1995) Response of failing canine and human heart cells to beta 2-adrenergic stimulation. Circulation 92:1612-8
Pitcher, J A; Payne, E S; Csortos, C et al. (1995) The G-protein-coupled receptor phosphatase: a protein phosphatase type 2A with a distinct subcellular distribution and substrate specificity. Proc Natl Acad Sci U S A 92:8343-7
Zolnierowicz, S; Csortos, C; Bondor, J et al. (1994) Diversity in the regulatory B-subunits of protein phosphatase 2A: identification of a novel isoform highly expressed in brain. Biochemistry 33:11858-67
Shima, H; Tohda, H; Aonuma, S et al. (1994) Characterization of the PP2A alpha gene mutation in okadaic acid-resistant variants of CHO-K1 cells. Proc Natl Acad Sci U S A 91:9267-71
Dutil, E M; Keranen, L M; DePaoli-Roach, A A et al. (1994) In vivo regulation of protein kinase C by trans-phosphorylation followed by autophosphorylation. J Biol Chem 269:29359-62
Tang, P M; Bondor, J A; Swiderek, K M et al. (1991) Molecular cloning and expression of the regulatory (RG1) subunit of the glycogen-associated protein phosphatase. J Biol Chem 266:15782-9

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