Regulation of the cardiac muscle ryanodine receptor by glutathione transferases

Abstract

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 Ca(2+) 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 α-helical bundle, centered around α-helix 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.

Differential Gene Expression of Cardiac Ion Channels in Human Dilated Cardiomyopathy

“…These proteins are capable of transitioning from the aqueous phase into a phospholipid membrane, where they can function as ion channels [44]. There are studies that propose a regulatory role for CLIC2 in the ryanodine receptor channel RYR2 [45,46]. RYR2 encodes a Ca 2+ channel protein anchored to the sarcoplasmic reticulum (SR) in cardiomyocytes that triggers Ca 2+ release to the cytoplasm during the contraction process.…”

Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6

“…Lastly, GSTO1 and ion chloride channel (CLIC1) bind to RyR channels (Donoso et al. ; Dulhunty et al ). Both binding sites are on the clamp region of RyR2, a region that undergoes significant structural changes with channel opening and which bind another important regulator, FKBP12.6 (Donoso et al.…”

“…ROS/RNS, normally produced in the heart, promote endogenous reversible RyR2-S-nitrosylation and S-glutathionylation (Donoso et al 2011). Lastly, GSTO1 and ion chloride channel (CLIC1) bind to RyR channels (Donoso et al 2011;Dulhunty et al 2011). Both binding sites are on the clamp region of RyR2, a region that undergoes significant structural changes with channel opening and which bind another important regulator, FKBP12.6 (Donoso et al 2011).…”

Glutathione S-Transferases in Pediatric Cancer

“…Knockout and transgenic mouse models were generated for many GST family members which helped to reveal the physiological function of GST isozymes (Elsby et al, 2003; Henderson and Wolf, 2011). Based on these and other model systems, many other activities are now associated with GSTs, including regulation of signaling pathways and anti-apoptotic activity by GSTP (Tew et al, 2011), anti- and pro-inflammatory functions of sigma-class GSTs (Flanagan and Smythe, 2011), activities of MGST1 related to mitochondria (Aniya and Imaizumi, 2011), regulation of the cardiac muscle ryanodine receptor (Dulhunty et al, 2011), and functions associated with asthma (Minelli et al, 2010). …”