scholarly journals Identification of a Glycogen Synthase Kinase-3β Inhibitor that Attenuates Hyperactivity in CLOCK Mutant Mice

ChemMedChem ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. 1593-1602 ◽  
Author(s):  
Alan P. Kozikowski ◽  
Hendra Gunosewoyo ◽  
Songpo Guo ◽  
Irina N. Gaisina ◽  
Richard L. Walter ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Mutant Mice ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Clock Mutant

scholarly journals Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β

Circulation ◽  
2019 ◽  
Vol 140 (14) ◽  
pp. 1188-1204 ◽  
Author(s):  
Laura Padrón-Barthe ◽  
María Villalba-Orero ◽  
Jesús M. Gómez-Salinero ◽  
Fernando Domínguez ◽  
Marta Román ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Right Ventricular ◽  
Glycogen Synthase ◽  
Transmembrane Protein ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Mutant Mice ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Arrhythmogenic Cardiomyopathy ◽  
Ventricular Cardiomyopathy

Background: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

Is Going for Cure in CML Targeting Aberrant Glycogen Synthase Kinase 3β?

2017 ◽  
Vol 18 (4) ◽  
pp. 396-404
Author(s):  
Concetta Saponaro ◽  
Michele Maffia ◽  
Nicola Renzo ◽  
Addolorata Coluccia
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Association of glycogen synthase kinase-3β with Parkinson’s disease (Review)

2014 ◽  
Vol 9 (6) ◽  
pp. 2043-2050 ◽  
Author(s):  
DA-WEI LI ◽  
ZHI-QIANG LIU ◽  
WEI-CHEN ◽  
MIN-YAO ◽  
GUANG-REN LI
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Melatonin Induces Melanogenesis in Human SK-MEL-1 Melanoma Cells Involving Glycogen Synthase Kinase-3 and Reactive Oxygen Species

2020 ◽  
Vol 21 (14) ◽  
pp. 4970
Author(s):  
Juan Perdomo ◽  
Carlos Quintana ◽  
Ignacio González ◽  
Inmaculada Hernández ◽  
Sara Rubio ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Glycogen Synthase ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Glycogen Synthase Kinase ◽  
Oxygen Species ◽  
Glycogen Synthase Kinase 3Β ◽  
Human Melanoma Cells

Melatonin is present in all living organisms where it displays a diversity of physiological functions. Attenuation of melanogenesis by melatonin has been reported in some mammals and also in rodent melanoma cells. However, melatonin may also stimulate melanogenesis in human melanoma cells through mechanisms that have not yet been revealed. Using the human melanoma cells SK-MEL-1 as a model, an increase in both tyrosinase activity and melanin was already observed at 24 h after melatonin treatment with maximal levels of both being detected at 72 h. This effect was associated with the induction in the expression of the enzymes involved in the synthesis of melanin. In this scenario, glycogen synthase kinase-3β seems to play a significant function since melatonin decreased its phosphorylation and preincubation with specific inhibitors of this protein kinase (lithium or BIO) reduced the expression and activity of tyrosinase. Blocking of PI3K/AKT pathway stimulated melanogenesis and the effect was suppressed by the inhibitors of glycogen synthase kinase-3β. Although melatonin is a recognized antioxidant, we found that it stimulates reactive oxygen species generation in SK-MEL-1 cells. These chemical species seem to be an important signal in activating the melanogenic process since the antioxidants N-acetyl-l-cysteine and glutathione decreased both the level and activity of tyrosinase stimulated by melatonin. Our results support the view that regulation of melanogenesis involves a cross-talk between several signaling pathways.

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