The structure of the C-terminal helical bundle in glutathione transferase M2-2 determines its ability to inhibit the cardiac ryanodine receptor

Hewawasam, Ruwani Punyakanthi; Liú, Dan; Dulhunty, Angela F.; Board, Philip G.

doi:10.1016/j.bcp.2010.04.019

Cited by 13 publications

(16 citation statements)

References 20 publications

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“…We attempted to identify the brain RyR isoform using the peptide GSTM2C H5-8, a C-terminal fragment of the musclespecific glutathione transferase (GSTM2). GSTM2C H5-8 specifically inhibits RyR2, but not RyR1 (Hewawasam et al, 2010), by binding to divergent region three of RyR2 (which has little sequence homology with RyR1 or RyR3) (Liu et al, 2012a). The brain RyRs failed to respond to 8 µM GSTM2C added after 2 μM H101Q CLIC2, suggesting that the channels were not RyR2.…”

Section: Sub-state Opening Induced By Wt Clic2 and H101q Clic2mentioning

confidence: 99%

Association of FK506 binding proteins with RyR channels – effect of CLIC2 binding on sub-conductance opening and FKBP binding

Richardson

Steele

Gallant

et al. 2017

Journal of Cell Science

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Ryanodine receptor (RyR) Ca channels are central to striated muscle function and influence signalling in neurons and other cell types. Beneficially low RyR activity and maximum conductance opening may be stabilised when RyRs bind to FK506 binding proteins (FKBPs) and destabilised by FKBP dissociation, with submaximal opening during RyR hyperactivity associated with myopathies and neurological disorders. However, the correlation with submaximal opening is debated and quantitative evidence is lacking. Here, we have measured altered FKBP binding to RyRs and submaximal activity with addition of wild-type (WT) CLIC2, an inhibitory RyR ligand, or its H101Q mutant that hyperactivates RyRs, which probably causes cardiac and intellectual abnormalities. The proportion of sub-conductance opening increases with WT and H101Q CLIC2 and is correlated with reduced FKBP-RyR association. The sub-conductance opening reduces RyR currents in the presence of WT CLIC2. In contrast, sub-conductance openings contribute to excess RyR 'leak' with H101Q CLIC2. There are significant FKBP and RyR isoform-specific actions of CLIC2, rapamycin and FK506 on FKBP-RyR association. The results show that FKBPs do influence RyR gating and would contribute to excess Ca release in this CLIC2 RyR channelopathy.

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Section: Sub-state Opening Induced By Wt Clic2 and H101q Clic2mentioning

confidence: 99%

Association of FK506 binding proteins with RyR channels – effect of CLIC2 binding on sub-conductance opening and FKBP binding

Richardson

Steele

Gallant

et al. 2017

Journal of Cell Science

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“…The glutathione transferases (GST) structural family modulates ryanodine receptor (RyR) isolated from muscles (cardiac and skeletal) [ 27 ]. GSTM2 is an inhibitor of cardiac RyR2 [ 28 , 29 ], and it has been shown to be expressed in human skeletal and cardiac muscle [ 30 ]. Hewawasam et al showed that exogenous treatment of neonatal cardiomyocytes with GSTM2 caused a reduction in spontaneous contractility [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiac Fibroblast-Induced Pluripotent Stem Cell-Derived Exosomes as a Potential Therapeutic Mean for Heart Failure

Kurtzwald-Josefson

Zeevi‐Levin

Rubchevsky

et al. 2020

IJMS

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The limited regenerative capacity of the injured myocardium leads to remodeling and often heart failure. Novel therapeutic approaches are essential. Induced pluripotent stem cells (iPSC) differentiated into cardiomyocytes are a potential future therapeutics. We hypothesized that organ-specific reprogramed fibroblasts may serve an advantageous source for future cardiomyocytes. Moreover, exosomes secreted from those cells may have a beneficial effect on cardiac differentiation and/or function. We compared RNA from different sources of human iPSC using chip gene expression. Protein expression was evaluated as well as exosome micro-RNA levels and their impact on embryoid bodies (EBs) differentiation. Statistical analysis identified 51 genes that were altered (p ≤ 0.05), and confirmed in the protein level, cardiac fibroblasts-iPSCs (CF-iPSCs) vs. dermal fibroblasts-iPSCs (DF-iPSCs). Several miRs were altered especially miR22, a key regulator of cardiac hypertrophy and remodeling. Lower expression of miR22 in CF-iPSCs vs. DF-iPSCs was observed. EBs treated with these exosomes exhibited more beating EBs p = 0.05. vs. control. We identify CF-iPSC and its exosomes as a potential source for cardiac recovery induction. The decrease in miR22 level points out that our CF-iPSC-exosomes are naïve of congestive heart cell memory, making them a potential biological source for future therapy for the injured heart.

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“…We discovered that members of GST structural family modulate ryanodine receptor (RyR) Ca 2+ release channels isolated from cardiac and skeletal muscle [ 9 ]. GSTM2 is specifically expressed in human skeletal and cardiac muscle [ 10 ] and was identified as an inhibitor of cardiac ryanodine receptor (RyR2), but not skeletal ryanodine receptor (RyR1), channels [ 11 , 12 ]. RyRs are a class of ligand-gated cation channels that are embedded in the membrane of intracellular Ca 2+ stores within endoplasmic reticulum (ER) in smooth muscle and non-muscle cells and sarcoplasmic reticulum (SR) in striated muscle fibers [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…RyRs are a class of ligand-gated cation channels that are embedded in the membrane of intracellular Ca 2+ stores within endoplasmic reticulum (ER) in smooth muscle and non-muscle cells and sarcoplasmic reticulum (SR) in striated muscle fibers [ 13 , 14 ]. The normal physiological function of GSTM2, in addition to its GSH conjugation, appears to be an anti-arrhythmic stabilization of RyR2 activity [ 11 , 12 ] which can be overridden by pro-arrhythmic factors in cardiac disorders. Therefore the selective inhibition of RyR2 by the C-terminal half of GSTM2 (GSTM2C) has significant clinical potential in the treatment of inherited and acquired RyR Ca 2+ -handling based arrhythmia where RyR2 channels are abnormally active, inducing arrhythmias and reducing Ca 2+ store filling during diastole and contractility.…”

Section: Introductionmentioning

confidence: 99%

“…We have shown that GSTM2 binds to RyR2 through its C-terminal domain and that this α-helical domain inhibits RyR2 function, but has no effect on skeletal muscle RyR1 Ca 2+ channels [ 11 ]. Helix 6 is a core element of GSTM2C that is essential for RyR2 inhibition [ 12 ]. Helix 6 has also been shown to play a key role in global folding of the cytosolic GST family [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes

et al. 2016

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The cardiac ryanodine receptor (RyR2) is an intracellular ion channel that regulates Ca2+ release from the sarcoplasmic reticulum (SR) during excitation–contraction coupling in the heart. The glutathione transferases (GSTs) are a family of phase II detoxification enzymes with additional functions including the selective inhibition of RyR2, with therapeutic implications. The C-terminal half of GSTM2 (GSTM2C) is essential for RyR2 inhibition, and mutations F157A and Y160A within GSTM2C prevent the inhibitory action. Our objective in this investigation was to determine whether GSTM2C can enter cultured rat neonatal ventricular cardiomyocytes and influence contractility. We show that oregon green-tagged GSTM2C (at 1 μM) is internalized into the myocytes and it reduces spontaneous contraction frequency and myocyte shortening. Field stimulation of myocytes evoked contraction in the same percentage of myocytes treated either with media alone or media plus 15 μM GSTM2C. Myocyte shortening during contraction was significantly reduced by exposure to 15 μM GSTM2C, but not 5 and 10 μM GSTM2C and was unaffected by exposure to 15 μM of the mutants Y160A or F157A. The amplitude of the Ca2+ transient in the 15 μM GSTM2C - treated myocytes was significantly decreased, the rise time was significantly longer and the decay time was significantly shorter than in control myocytes. The Ca2+ transient was not altered by exposure to Y160A or F157A. The results are consistent with GSTM2C entering the myocytes and inhibiting RyR2, in a manner that indicates a possible therapeutic potential for treatment of arrhythmia in the neonatal heart.

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The structure of the C-terminal helical bundle in glutathione transferase M2-2 determines its ability to inhibit the cardiac ryanodine receptor

Cited by 13 publications

References 20 publications

Association of FK506 binding proteins with RyR channels – effect of CLIC2 binding on sub-conductance opening and FKBP binding

Association of FK506 binding proteins with RyR channels – effect of CLIC2 binding on sub-conductance opening and FKBP binding

Cardiac Fibroblast-Induced Pluripotent Stem Cell-Derived Exosomes as a Potential Therapeutic Mean for Heart Failure

The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes

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