The parent project for this FIRCA application studies three aims: 1) To characterize the interaction between FKBP12 and the skeletal muscle ryanodine receptor (RyR1); 2) To identify the FKBP associated with cardiac muscle ryanodine receptor (RyR2) and analyze its functional role; and 3) To determine whether the proline isomerase activity of FKBP12 plays a role in modulating cardiac and skeletal muscle ryanodine receptor function. This proposed collaboration will: 1) Characterize the role of FKBP12 in facilitating coupled gating between two or more skeletal muscle ryanodine receptors (RyR1); 2) Examine the role of FKBP12 in the activation of RyR1 by the voltage-dependent calcium channel (VDCC)/dihydropyridine receptor during E-C coupling in skeleta muscle; and 3) Determine whether FKBP effects activation of the cardiac RyR2 during E-C coupling in cardiac muscle. The FIRCA proposal makes use of new perspectives based on recent experiments identifying sequences in the II-III loop of the skeletal VDCC as activators of RyR1 during E-C coupling. The general aim is to exploit the remarkable powers of combining the biophysical investigations of individual openings of Ca channels produced in exogenous expression systems (like sf 9 cells). The investigators will use single channel measurements in artificial bilayers. The working hypothesis is that receptor/channel cooperation is central in modulating channel responses. They suggest that FKBP is a novel endogenous regulator of skeletal muscle RyR1 With FKBP12 associated to it, two RyR1/Ca release channels gate cooperatively resulting in twice the normal full conductance openings. To better understand how FKBP is involved in regulating RyR1/Ca release channel function, they propose: 1) to use drugs (FK506) and rapamycin) that inhibit the effects of FKBP12 on channel gating; and 2) determine whether mutations in the FKBP12 binding site on RyR1 affect coupled gating.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW000949-02
Application #
2910801
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
2
Fiscal Year
1999
Total Cost
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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