The long-term goal of this project is to improve our understanding of redox regulation of an intracellular calcium release channel (the ryanodine receptor) in skeletal muscle by reactive nitrogen species (RNS). All three isoforms of nitric oxide synthase (NOS) have been identified in skeletal muscle. Nitric oxide and related species (collectively termed reactive nitrogen species) produced endogenously in muscle have been shown to influence force generation. We hypothesize that the effects of RNS on muscle contractility occur in part through the ryanodine receptor, which contains regulatory thiols.
The specific aims of this proposal are: 1) Define the subcellular locations of each isoform of NOS in relation to the ryanodine receptor 2) Assess the effects of reactive nitrogen species on channel activity in vitro and in muscle cell culture systems and 3) Determine the underlying molecular mechanism(s) of regulation. Our results may lead to new insights into regulation of Ca2+ homeostasis in muscle and to the dysregulation of Ca2+ characteristic of disease states such as respiratory failure and rhabdomyolysis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL004053-03
Application #
6388545
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M1))
Program Officer
Commarato, Michael
Project Start
1999-08-15
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$124,848
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Qi, Wen-Ning; Chen, Long-En; Zhang, Li et al. (2004) Reperfusion injury in skeletal muscle is reduced in inducible nitric oxide synthase knockout mice. J Appl Physiol 97:1323-8
Eu, Jerry P; Hare, Joshua M; Hess, Douglas T et al. (2003) Concerted regulation of skeletal muscle contractility by oxygen tension and endogenous nitric oxide. Proc Natl Acad Sci U S A 100:15229-34
Young, Stephen L; Evans, Katherine; Eu, Jerry P (2002) Nitric oxide modulates branching morphogenesis in fetal rat lung explants. Am J Physiol Lung Cell Mol Physiol 282:L379-85
Sun, J; Xu, L; Eu, J P et al. (2001) Classes of thiols that influence the activity of the skeletal muscle calcium release channel. J Biol Chem 276:15625-30
Sun, J; Xin, C; Eu, J P et al. (2001) Cysteine-3635 is responsible for skeletal muscle ryanodine receptor modulation by NO. Proc Natl Acad Sci U S A 98:11158-62
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