Previous studies have shown that, like many other proteins, amino acid residues of potassium channels are subject to oxidation by reactive oxyge species. Oxidation of amino acid residues, especially of cysteine residues, is well documented. Methionine can be readily oxidized to form methionine sulfoxide. Oxidation of methionine is unique in that it is reversible and that reduction of oxidized methionine requires an enzyme, methionine sulfoxide reductase (MsrA). The reversibility of methionine oxidation catalyzed by MsrA suggests that it could act as an important cellular regulatory mechanism. Preliminary results indeed suggest that oxidation of methionine residues in Shaker potassium channels has dramatic effects on the channel activation and deactivation. This project will establish the dynamic functional role of methionine oxidation as a key player in regulation of cellular excitability. Shaker potassium channels will be expressed in Xenopus oocytes and their macroscopic and single-channel current properties examined using the two-electrode voltage clamp and patch-clamp methods. The effects of methionine mutations and MsrA co-expression will be quantitatively assayed to elucidate the biophysical mechanisms involved. The importance of methionine oxidation an its reversal by MsrA in a variety of other potassium channels and voltage-dependent calcium channels will also be examined. Results from the proposed research will establish a novel cellular excitability mechanism involving methionine oxidation and reduction.
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