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Regulation of the cardiac muscle ryanodine receptor by glutathione transferases

Dulhunty, Angela; Hewawasam, Ruwani; Liu, Dan; Casarotto, Marco; Board, Philip

Description

Glutathione transferases (GSTs) are generally recognized for their role in phase II detoxification reactions. However, it is becoming increasingly apparent that members of the GST family also have a diverse range of other functions that are, in general, unrelated to detoxification. One such action is a specific inhibition of the cardiac isoform of the ryanodine receptor (RyR2) intracellular Ca2+ release channel. In this review, we compare functional and physical interactions between members of...[Show more]

dc.contributor.authorDulhunty, Angela
dc.contributor.authorHewawasam, Ruwani
dc.contributor.authorLiu, Dan
dc.contributor.authorCasarotto, Marco
dc.contributor.authorBoard, Philip
dc.date.accessioned2015-12-10T23:35:24Z
dc.identifier.issn0360-2532
dc.identifier.urihttp://hdl.handle.net/1885/69850
dc.description.abstractGlutathione transferases (GSTs) are generally recognized for their role in phase II detoxification reactions. However, it is becoming increasingly apparent that members of the GST family also have a diverse range of other functions that are, in general, unrelated to detoxification. One such action is a specific inhibition of the cardiac isoform of the ryanodine receptor (RyR2) intracellular Ca2+ release channel. In this review, we compare functional and physical interactions between members of the GST family, including GSTO1-1, GSTA1-1, and GSTM2-2, with RyR2 and with the skeletal isoform of the ryanodine receptor (RyR1). The active part of the muscle-specific GSTM2-2 is localized to its nonenzymatic C-terminal αhelical bundle, centered around αhelix 6. The GSTM2-2 binding site is in divergent region 3 (DR3 region) of RyR2. The sequence differences between the DR3 regions of RyR1 and RyR2 explain the specificity of the GSTs for one isoform of the protein. GSTM2-2 is one of the few known endogenous inhibitors of the cardiac RyR and is likely to be important in maintaining low RyR2 activity during diastole. We discuss interactions between a nonenzymatic member of the GST structural family, the CLIC-2 (type 2 chloride intracellular channel) protein, which inhibits both RyR1 and RyR2. The possibility that the GST and CLIC2 proteins bind to different sites on the RyR, and that different structures within the GST and CLIC proteins bind to RyR channels, is discussed. We conclude that the C-terminal part of GSTM2-2 may provide the basis of a therapeutic compound for use in cardiac disorders.
dc.publisherInforma Healthcare
dc.sourceDrug Metabolism Reviews
dc.subjectKeywords: calcium channel blocking agent; calcium ion; chloride channel; glutathione transferase; glutathione transferase A1; glutathione transferase M2; glutathione transferase omega 1; ryanodine receptor; ryanodine receptor 1; ryanodine receptor 2; ryanodine rece CLIC proteins; heart failure; Inhibitors of cardiac ryanodine receptor; muscle-specific glutathione transferase; singlechannel recording; the DR3 region of RyR2; three-dimensional structure
dc.titleRegulation of the cardiac muscle ryanodine receptor by glutathione transferases
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume43
dc.date.issued2011
local.identifier.absfor060110 - Receptors and Membrane Biology
local.identifier.ariespublicationf2965xPUB2140
local.type.statusPublished Version
local.contributor.affiliationDulhunty, Angela, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationHewawasam, Ruwani, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationLiu, Dan, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationCasarotto, Marco, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationBoard, Philip, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue2
local.bibliographicCitation.startpage236
local.bibliographicCitation.lastpage252
local.identifier.doi10.3109/03602532.2010.549134
local.identifier.absseo970111 - Expanding Knowledge in the Medical and Health Sciences
dc.date.updated2016-02-24T08:22:27Z
local.identifier.scopusID2-s2.0-79954625549
local.identifier.thomsonID000289562800010
CollectionsANU Research Publications

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