Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Tsukamoto, Osamu; Kitakaze, Masafumi

doi:10.1253/circj.cj-13-0627

Cited by 33 publications

(26 citation statements)

References 66 publications

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“…MLC phosphorylation is thought to be associated with the disruption of TJ assembly and impairment of intestinal epithelial barrier function [37, 38]. MLC phosphorylation is induced by various kinases, including MLCK, ROCK, and PKC [39]. Several groups have reported that increased production and activation of MLCK by TNF-α modulate MLC phosphorylation in Caco-2 cells [12, 32].…”

Section: Discussionmentioning

confidence: 99%

Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

Watari¹,

Sakamoto²,

Hisaie³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Although proinflammatory cytokine–induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. Methods: To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Results: Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Conclusion: Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation.

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Section: Discussionmentioning

confidence: 99%

Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

Watari¹,

Sakamoto²,

Hisaie³

et al. 2017

Cell Physiol Biochem

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“…The regulation of cytoskeleton dynamics by Ca 2+ /CaM, either activating MLCK, which phosphorylates the light-chain of myosin, or negatively acting on microtubules has long been recognized as reviewed by Means and collaborators decades ago using Sertoli cells as an experimental model [99]. MLCK is a CaM-dependent kinase that plays a fundamental role regulating cell migration and function as a key player in smooth, skeletal, and cardiac muscle contraction (reviewed in [41,100,101]). Inhibition of MLCK and CaM by specific inhibitors (ML-7 and W-7, respectively), prevents the migration of myofibroblasts induced by cardiotrophin-1 participating in the repair of scars after infarction [68].…”

Section: Cam and Cytoskeleton Dynamicsmentioning

confidence: 99%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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“…Aside from affecting MMP-2mediated degradation, other groups have identified MLC modifications in other important physiological roles (6,8,9,11). Nitration of MLC has been reported in the process of vascular aging (17,18), and the phosphorylation of MLC2 controls the sensitivity of myofilaments to calcium in the regulation of heart contractility (19)(20)(21).…”

Section: L-name Improves Doxycycline and Ml-7 Cardioprotection From Omentioning

confidence: 99%

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

et al. 2018

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Matrix metalloproteinase-2 (MMP-2) mediated degradation of myosin light chain 1 (MLC1) and troponin I (TnI) contributes to myocardial ischemia/reperfusion (I/R) injury. Modifications of MLC1 triggered by oxidative stress are mediated by myosin light chain kinase (MLCK), nitric oxide synthase (NOS), and MMP-2. Previous studies have shown that inhibiting both MLCK and MMP-2 protects against I/R injury. Here, we hypothesized that the addition of NOS inhibitor (L-NAME) at subprotective concentration to the mixture of subprotective concentrations of ML-7 and doxycycline (Doxy), will increase a synergistic cardioprotection of Doxy and ML-7 during I/R. Isolated rat hearts were subjected to global ischemia without or with administration of the mixture of inhibitors. Markers of I/R injury were measured in hearts and coronary effluents. Addition of L-NAME to the mixture of Doxy and ML-7 led to full recovery of heart contractility in comparison to combination of Doxy and ML-7. Improved heart contractility was associated with reduced degradation of TnI and MLC1. The combined administration of NOS, MMP-2 and MLCK inhibitors provides a novel strategy to protect heart from I/R injury.

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Biochemical and Physiological Regulation of Cardiac Myocyte Contraction by Cardiac-Specific Myosin Light Chain Kinase

Cited by 33 publications

References 66 publications

Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

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