Nitrosylation of Cysteine Residues Activates the Skeletal Muscle Calcium Release Channel

PI: Jonathan Stamler
Howard Hughes Medical Institute and Duke University Medical Center

Background: Oxidation/reduction induced-modifications of the cysteine residues in proteins have emerged as a molecular mechanism which drives many cellular processes including DNA transcription, protein folding, and enzyme function. A great deal of on-going research suggests that redox-related modifications of ion channels may be involved in a variety of complex physiological responses such as constriction and dilation of blood vessels, muscle contraction, and synapse function. However, the nature of redox-related protein modification which occurs is unclear. This change could be a "redox signal" or perhaps just an oxidative stress response. Oxygen concentration changes have been shown to modulate ion channel activities with NO playing a possible role; however, the molecular mechanisms have not been determined.

Advance: In this study, the role of oxygen concentration in NO-redox control of the skeletal muscle intracellular calcium release channel was explored under ambient oxygen concentration and a much lower concentration such as that normally found in muscle tissue. The results show exposure of the channel to ambient oxygen leads to oxidative changes that are likely to be artificial and that the NO concentration necessary to activate the channel in ambient oxygen is physiologically unattainable. The experiments demonstrate the importance of tissue oxygen concentration in ion channel function and demonstrate that NO activates the channel by interacting with a single cysteine residue in a reaction called S-nitrosylation.

Implication: This work provides a model for future studies of redox-related signaling that may broadly apply to ion channels and membrane proteins. Understanding the mechanisms of these channels and how they can be altered are the first steps toward designing drugs and treatments for diseases that result from damaged or inoperable ion channels.

Citation:Eu JP, Sun J, Xu L, Stamler JS, Meissner G. The skeletal muscle calcium release channel: coupled O2 sensor and NO signaling functions. Cell. 2000 Aug 18;102(4):499-509.