Local Signals and Macromolecular Architecture in Heart

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Heart Failure


T. B. Rogers
R. J. Bloch
W. J. Lederer

Molecular Genetics
Cell Biology 

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Project 1: Rogers

Phosphatases, Local Structures
and Signaling in Heart

Approaches and Results

This project uses a series of complementary approaches including voltage clamp, high resolution confocal imaging, adenoviral gene transfer, and biochemical analyses to critically examine the links between local phosphorylation, cytoskeletal structures, and Ca2+ signaling in heart.

One experimental approach is defining the functional sites to which the phosphatase PP2A is targeted in cardiac myocytes. This series will use a combination of intact cell studies combined with proteomic analyses.

We are also working on identifying the specific amino acid sequence motifs in PP2A B-targeting subunits that determine its segregation to discrete cardiac cell structures. Virus directed gene transfer of GFP fusion proteins is being used in this analysis.

The role of phosphatases and t-tubule cytoskeleton proteins in the regulation of L-type Ca2+ channel activity is also being studied through a combination of voltage clamp and molecular genetics methods (see Figure on right). This study is being performed in normal and heart failure animal models.

We are also examining alterations in PP2A targeting evoked by gene tansfection methods change signal transduction cascades.

Thus this project is defining the links between phosphatase subcellular targeting, cytoskeletal architecture, and Ca2+ signaling in cardiac myocytes.



Dynamic modulation
Dynamic modulation of Ca2+ signaling by phosphatase inhibition.
Single cell voltage clamp studies were used to show phosphatase inhibition. The figure shows that both [Ca2+]i transient and whole cell Ca2+ current, ICa, are markedly increased after application of phosphatase inhibitor, calyculin A. This reveals the functional significance of a phosphatase/kinase balance in controlling cardiac cell function.

Approaches and Results


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