Interaction of calcium/calmodulin-dependent protein kinase IIδC with sorcin indirectly modulates ryanodine receptor function in cardiac myocytes

Anthony, Diana F.; Beattie, James; Paul, Andrew; Currie, Susan

doi:10.1016/j.yjmcc.2007.07.003

Cited by 24 publications

(23 citation statements)

References 31 publications

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“…In addition, dephosphorylated sorcin significantly inhibits CaMKII activity [62], [63]. Only a very small fraction of protein interactors is shared by sorcin and calmodulin [64].…”

Section: Discussionmentioning

confidence: 99%

Sorcin Links Calcium Signaling to Vesicle Trafficking, Regulates Polo-Like Kinase 1 and Is Necessary for Mitosis

et al. 2014

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Sorcin, a protein overexpressed in many multi-drug resistant cancers, dynamically localizes to distinct subcellular sites in 3T3-L1 fibroblasts during cell-cycle progression. During interphase sorcin is in the nucleus, in the plasma membrane, in endoplasmic reticulum (ER) cisternae, and in ER-derived vesicles localized along the microtubules. These vesicles are positive to RyR, SERCA, calreticulin and Rab10. At the beginning of mitosis, sorcin-containing vesicles associate with the mitotic spindle, and during telophase are concentrated in the cleavage furrow and, subsequently, in the midbody. Sorcin regulates dimensions and calcium load of the ER vesicles by inhibiting RYR and activating SERCA. Analysis of sorcin interactome reveals calcium-dependent interactions with many proteins, including Polo-like kinase 1 (PLK1), Aurora A and Aurora B kinases. Sorcin interacts physically with PLK1, is phosphorylated by PLK1 and induces PLK1 autophosphorylation, thereby regulating kinase activity. Knockdown of sorcin results in major defects in mitosis and cytokinesis, increase in the number of rounded polynucleated cells, blockage of cell progression in G2/M, apoptosis and cell death. Sorcin regulates calcium homeostasis and is necessary for the activation of mitosis and cytokinesis.

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“…In addition, dephosphorylated sorcin significantly inhibits CaMKII activity [62], [63]. Only a very small fraction of protein interactors is shared by sorcin and calmodulin [64].…”

Section: Discussionmentioning

confidence: 99%

Sorcin Links Calcium Signaling to Vesicle Trafficking, Regulates Polo-Like Kinase 1 and Is Necessary for Mitosis

et al. 2014

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“…In addition to the previous study14 that showed that aldolase A was recruited to the SR component by calpain-3, our results suggest that calpain-3 plays a role in stabilizing RyR associated protein complexes in the SR. When Ca 2+ is discharged to the cytosol, it is possible that calpain-3 functions as a fine tuning element in coordination with RyR and other molecules in the SR. Sorcin, five EF-hand motifs (called “penta EF-hand motif (PEF) domain”) containing Ca 2+ binding molecule, has been reported to modulate the open probability of RyR through Ca 2+ /calmodulin-dependent protein kinase II 17,18. As calpain-3 also has PEF domain, calpain-3 might have a similar effect.…”

Section: Discussionmentioning

confidence: 99%

Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles

Ojima

Ono

Ottenheijm

et al. 2011

Journal of Molecular Biology

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Mutations in CAPN3/Capn3, which codes for skeletal muscle-specific calpain-3/p94 protease, are responsible for limb-girdle muscular dystrophy type 2A (LGMD2A). Using "knock-in" (referred to as Capn3 CS/CS ) mice, in which the endogenous calpain-3 is replaced with a mutant calpain-3:C129S, that is proteolytically inactive but structurally intact calpain-3, our previous studies demonstrated that loss of calpain-3 protease activity caused muscular dystrophy. However, compared to Capn3 null (Capn3 −/− ) mice, Capn3 CS/CS mice showed less severe dystrophic symptoms. This suggests that calpain-3 also has a non-proteolytic function. This study aimed to elucidate non-protease calpain-3 functions, by comparison of Capn3 CS/CS mice with Capn3 −/− mice. We found that calpain-3 is a component of the sarcoplasmic reticulum (SR), and that calpain-3 interacts with, but does not proteolyze, typical SR components such as ryanodine receptor and calsequestrin. Furthermore, Capn3 CS/CS mice showed that the non-enzymatic role of calpain-3 is required for proper Ca 2+ efflux from the SR to cytosol during contraction of muscles. These results indicate that calpain-3 functions as a non-enzymatic element for the Ca 2+ efflux machinery in the SR rather than as a protease. Thus, defects of the non-enzymatic function of calpain-3 must also be involved in pathogenesis of LGMD2A.

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“…In addition, RyR2 is also regulated by protein kinase A and Ca 2 + /calmodulin dependent protein kinase II (CaMKII) (Anthony et al, 2007). The RyR channels act as redox sensors as they are regulated by redox state of highly reactive cysteine residues (Eu et al, 2000;Pessah et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of RyR2 in Hypoxic/Reperfusion Injury

Kesherwani

Agrawal²

2012

Journal of Neurotrauma

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Calcium influx into cells is responsible for initiating the cell death in neuronal tissue after hypoxic injury. Changes in intracellular calcium with subsequent increased expression of ryanodine receptor 2 (RyR2) are hypothesized to cause cell death after hypoxic injury. In the present study we have examined the time-dependent changes of RyR2 expression in hypoxic/reperfusion injury of spinal cord dorsal column. In this study we used western blotting, real time PCR (RT-PCR) and immunohistochemistry to examine changes in protein and gene expression of RyR2 after spinal cord injury (SCI) in the rat. Quantitative immunoblotting showed increase in the expression of RyR2 at 4 h during hypoxic/reperfusion injury of dorsal column. Moreover, RT-PCR showed 36-fold increases in mRNA of RyR2 after 4 h of hypoxic injury of white matter. By double immunofluorescence staining, RyR2 was localized on axons and astrocytes in the white matter of the spinal cord. After treatment with KN-62; (inhibitor of CaMKII) and SP600125 (inhibitor of JNK), there is a significant reduction in the expression of RyR2, indicating the role of these molecules in RyR2 regulation. Further removal of extracellular calcium does not have significant effect on RyR2 expression and phosphorylation of CaMKII, which was further confirmed by treatment with intracellular Ca(++) chelator BAPTA-AM. Finally, bioassay with quantitative analysis showed that treatment with inhibitor significantly reduced the cellular oxidative stress suggesting RyR2 is responsible for increased cellular oxidative load. In summary, we provide evidence that RyR2 gene and protein expression in astrocyte and axons is markedly increased after hypoxic injury. Further CaMKII/JNK pathway upregulates RyR2 expression after hypoxic injury. Therefore we propose that inhibitors of CaMKII/JNK pathway would reduce the cellular oxidative load and thereby have a neuroprotective role.

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Interaction of calcium/calmodulin-dependent protein kinase IIδC with sorcin indirectly modulates ryanodine receptor function in cardiac myocytes

Cited by 24 publications

References 31 publications

Sorcin Links Calcium Signaling to Vesicle Trafficking, Regulates Polo-Like Kinase 1 and Is Necessary for Mitosis

Sorcin Links Calcium Signaling to Vesicle Trafficking, Regulates Polo-Like Kinase 1 and Is Necessary for Mitosis

Non-Proteolytic Functions of Calpain-3 in Sarcoplasmic Reticulum in Skeletal Muscles

Upregulation of RyR2 in Hypoxic/Reperfusion Injury

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