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Gangopadhyay, Samudra Saurabh

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Gangopadhyay

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Samudra Saurabh

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Gangopadhyay, Samudra Saurabh
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    Systemic administration of Follistatin288 increases muscle mass and reduces fat accumulation in mice
    (Nature Publishing Group, 2013) Gangopadhyay, Samudra Saurabh
    The present study describes the physiological response associated with daily subcutaneous injection of mice with recombinant follistatin288. This systemic administration of follistatin288 increases the follistatin levels in serum, indicating that the protein enters the circulation. The data suggest that a dose-dependent increase in body lean mass also occurs, together with an increase in muscle mass, possibly as a result of an increase in the size of the muscle fibers. After thirteen weeks of treatment, metabolic changes were observed; additionally, the switching of muscle fiber types was also apparent through myosin heavy chain remodeling, implying that changes are occurring at the molecular level. Furthermore, an increase in the muscle mass was associated with a significant decrease in the body fat mass. Overall, this study raises the possibility for the use of follistatin288 as an agent to treat muscle wasting diseases and/or to restrict fat accumulation by systemic administration of the protein.
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    JunB Mediates Basal- and TGFβ1-Induced Smooth Muscle Cell Contractility
    (Public Library of Science, 2013) Ramachandran, Aruna; Gangopadhyay, Samudra Saurabh; Krishnan, Ramaswamy; Ranpura, Sandeep A.; Rajendran, Kavitha; Ram-Mohan, Sumati; Mulone, Michelle; Gong, Edward M.; Adam, Rosalyn
    Smooth muscle contraction is a dynamic process driven by acto-myosin interactions that are controlled by multiple regulatory proteins. Our studies have shown that members of the AP-1 transcription factor family control discrete behaviors of smooth muscle cells (SMC) such as growth, migration and fibrosis. However, the role of AP-1 in regulation of smooth muscle contractility is incompletely understood. In this study we show that the AP-1 family member JunB regulates contractility in visceral SMC by altering actin polymerization and myosin light chain phosphorylation. JunB levels are robustly upregulated downstream of transforming growth factor beta-1 (TGFβ1), a known inducer of SMC contractility. RNAi-mediated silencing of JunB in primary human bladder SMC (pBSMC) inhibited cell contractility under both basal and TGFβ1-stimulated conditions, as determined using gel contraction and traction force microscopy assays. JunB knockdown did not alter expression of the contractile proteins α-SMA, calponin or SM22α. However, JunB silencing decreased levels of Rho kinase (ROCK) and myosin light chain (MLC20). Moreover, JunB silencing attenuated phosphorylation of the MLC20 regulatory phosphatase subunit MYPT1 and the actin severing protein cofilin. Consistent with these changes, cells in which JunB was knocked down showed a reduction in the F:G actin ratio in response to TGFβ1. Together these findings demonstrate a novel function for JunB in regulating visceral smooth muscle cell contractility through effects on both myosin and the actin cytoskeleton.
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    Phosphorylation at \(Ser^{26}\) in the ATP-Binding Site of \(Ca^{2+}\)/Calmodulin-Dependent Kinase II as a Mechanism for Switching off the Kinase Activity
    (Portland Press Ltd., 2013) Yilmaz, Mehtap; Gangopadhyay, Samudra Saurabh; Leavis, Paul Clifton; Grabarek, Zenon; Morgan, Kathleen G.
    CaMKII \((Ca^{2+}\)/calmodulin-dependent kinase II) is a serine/threonine phosphotransferase that is capable of long-term retention of activity due to autophosphorylation at a specific threonine residue within each subunit of its oligomeric structure. The \(\gamma\) isoform of CaMKII is a significant regulator of vascular contractility. Here, we show that phosphorylation of CaMKII \(\gamma\) at \(Ser^{26}\), a residue located within the ATP-binding site, terminates the sustained activity of the enzyme. To test the physiological importance of phosphorylation at \(Ser^{26}\), we generated a phosphospecific \(Ser^{26}\) antibody and demonstrated an increase in \(Ser^{26}\) phosphorylation upon depolarization and contraction of blood vessels. To determine if the phosphorylation of \(Ser^{26}\) affects the kinase activity, we mutated \(Ser^{26}\) to alanine or aspartic acid. The S26D mutation mimicking the phosphorylated state of CaMKII causes a dramatic decrease in \(Thr^{287}\) autophosphorylation levels and greatly reduces the catalytic activity towards an exogenous substrate (autocamtide-3), whereas the S26A mutation has no effect. These data combined with molecular modelling indicate that a negative charge at \(Ser^{26}\) of CaMKII \(\gamma\) inhibits the catalytic activity of the enzyme towards its autophosphorylation site at \(Thr^{287}\) most probably by blocking ATP binding. We propose that \(Ser^{26}\) phosphorylation constitutes an important mechanism for switching off CaMKII activity.