Functional role of hyperreactive sulfhydryl moieties within the ryanodine receptor complex.
Several laboratories using chemically heterogeneous sulfhydryl modifying agents have shown that sarcoplasmic reticulum (SR) Ca2+ channels known as ryanodine receptors (RyRs) are especially sensitive to modification of functionally important cysteine residues. The functional consequence of sulfhydryl modification of RyRs can include phases of activation and inhibition that are very much dependent on the concentration of the reagent used, the length of exposure, and the nature of the chemical reaction the reagent undertakes with sulfhydryl groups. Most challenging is understanding the relationship for how specific sulfhydryl moieties ascribe specific aspects of RyR function. Considering the structural complexity of the RyR complex with its associated proteins, this task is likely to be a formidable one. A small number of hyperreactive thiols have been shown to exist within the RyR complex. Their functional role does not appear to impact directly on channel gating. Rather hyperreactive cysteine (Cys) moieties may represent biochemical components of a redox sensor that conveys information about localized changes in redox potential produced by physiologic (e.g., glutathione, nitric oxide) and pathophysiologic (quinones, reactive oxygen species) channel modulators to the Ca2+ release process. The molecular and functional details of such a redox sensor remains to be elucidated.
Pessah
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Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis 95616, USA. inpessah@ucdavis.edu
Feng
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D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002352:Carrier Proteins; D003553:Cystine / Q000378:metabolism*; D005246:Feedback; D005978:Glutathione / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport / Q000187:drug effects; D046911:Macromolecular Substances; D019216:Metals, Heavy / Q000494:pharmacology; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009569:Nitric Oxide / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011487:Protein Conformation / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000494:pharmacology / Q000502:physiology*
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D046911:Macromolecular Substances; D019216:Metals, Heavy; D009124:Muscle Proteins; D011809:Quinones; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; C498269:TRDN protein, human; C498271:Trdn protein, rat; C070048:triadin; D009569:Nitric Oxide; D003553:Cystine; D000252:Calcium-Transporting ATPases; D005978:Glutathione