Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation.
Several ion channels are reportedly redox responsive, but the molecular basis for the changes in activity is not known. The mechanism of nitric oxide action on the cardiac calcium release channel (ryanodine receptor) (CRC) in canines was explored. This tetrameric channel contains approximately 84 free thiols and is S-nitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per CRC subunit) led to progressive channel activation that was reversed by denitrosylation. In contrast, oxidation of 20 to 24 thiols per CRC (5 or 6 per subunit) had no effect on channel function. Oxidation of additional thiols (or of another class of thiols) produced irreversible activation. The CRC thus appears to be regulated by poly-S-nitrosylation (multiple covalent attachments), whereas oxidation can lead to loss of control. These results reveal that ion channels can differentiate nitrosative from oxidative signals and indicate that the CRC is regulated by posttranslational chemical modification(s) of sulfurs.
Xu
L
L
Department of Biochemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Eu
J P
JP
Meissner
G
G
Stamler
J S
JS
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004285:Dogs; D004553:Electric Conductivity; D005033:Ethylmaleimide / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D008081:Liposomes / Q000378:metabolism; D008623:Mercaptoethanol; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation; D009603:Nitroso Compounds / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D011510:Proteolipids / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D026422:S-Nitrosoglutathione; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds / Q000378:metabolism
D008081:Liposomes; D009603:Nitroso Compounds; D011510:Proteolipids; D019837:Ryanodine Receptor Calcium Release Channel; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds; C020485:proteoliposomes; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C002385:linsidomine; D008623:Mercaptoethanol; C032635:S-nitrosomercaptoethanol; C021315:S-nitrosocysteine; D008981:Molsidomine; D005978:Glutathione; D006152:Cyclic GMP; D003545:Cysteine; D005033:Ethylmaleimide; D002118:Calcium; D004229:Dithiothreitol