The ryanodine receptor (RyR)/calcium (Ca) release channel is required for excitation- contraction (EC) coupling in cardiac and skeletal muscle. Although the primary structures of the RyR/Ca release channels have been determined from cDNA cloning, most of the functional domains of the channels have not yet been identified. Therefore, how channel properties are determined by the channel structure is not well understood. The goal of this proposal is to use the cloned expressed RyR to increase our knowledge of how fundamental channel properties are related to structure.
The aims of this proposal are made feasible by the development of a model system for heterologous functional expression of RyR in insect cells and by the identification of an endogenous channel associated protein, FKBP, that modulates channel gating specifically by: 1) increasing the frequency of the full conductance state of the channel; 2) increasing mean open time (t); and 3) decreasing open probability (Po) after caffeine activation.
Aim 1 proposes to identify the FKBP binding site on skeletal RyR1.
Aim 2 proposes to characterize the modulation of cardiac RyR2 gating by a novel form of FKBP.
Aim 3 proposes to determine whether the proline isomerase activity of FKBP is required for channel modulation. RyR molecules containing mutations in FKBP binding domains will be expressed in muscle cells that lack the RyR gene to determine the physiologic role of FKBP in the RyR channel complex. Elucidation of the structure/function relationships of RyR will help us understand the regulation of Ca release from sarcoplasmic reticulum.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056180-06
Application #
6184198
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Lymn, Richard W
Project Start
1996-04-20
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
6
Fiscal Year
2000
Total Cost
$357,249
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
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Andersson, Daniel C; Marks, Andrew R (2010) Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile failure in heart and skeletal muscle. Drug Discov Today Dis Mech 7:e151-e157

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