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mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel
| Content Provider | Scilit |
|---|---|
| Author | Meissner, Gerhard Huang, Tai-Qin Zou, Min-Xu Pasek, Daniel A. |
| Copyright Year | 2015 |
| Description | Journal: Journal of Receptor, Ligand and Channel Research MTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel Tai-Qin Huang,* Min-Xu Zou,* Daniel A Pasek, Gerhard Meissner Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA *These authors contributed equally to this work Simultaneous substitution of three amino acid residues in the calmodulin binding domain (W3587A/L3591D/F3603A, ADA) of the cardiac ryanodine receptor ion channel (RyR2) impairs calmodulin inhibition of RyR2 and causes cardiac hypertrophy and early death of Ryr2ADA/ADA mice. To determine the physiological significance of growth promoting signaling molecules, the protein and phosphorylation levels of Ser/Thr kinase mTOR and upstream and downstream signaling molecules were determined in hearts of wild-type and Ryr2ADA/ADA mice. Phosphorylation of mTOR at Ser-2448, and mTOR downstream targets p70S6 kinase at Thr-389, S6 ribosomal protein at Ser-240/244, and 4E-BP1 at Ser-65 were increased. However, there was no increased phosphorylation of mTOR upstream kinases PDK1 at Ser-241, AKT at Thr-308, AMPK at Thr-172, and ERK1/2 at Thr-202/Tyr204. To confirm a role for mTOR signaling in the development of cardiac hypertrophy, rapamycin, an inhibitor of mTOR, was injected into wild-type and mutant mice. Rapamycin decreased mouse heart-to-body weight ratio, improved cardiac performance, and decreased phosphorylation of mTOR and downstream targets p70S6K and S6 in 10-day-old Ryr2ADA/ADA mice but did not extend longevity. Taken together, the results link a dysfunctional RyR2 to an altered activity of signaling molecules that regulate cardiac growth and function. Keywords: calmodulin, cardiac hypertrophy, rapamycin, RyR2 |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547478/pdf https://www.dovepress.com/getfile.php?fileID=25135 |
| Ending Page | 51 |
| Page Count | 9 |
| Starting Page | 43 |
| e-ISSN | 1178699X |
| DOI | 10.2147/jrlcr.s78410 |
| Journal | Journal of Receptor, Ligand and Channel Research |
| Volume Number | 8 |
| Language | English |
| Publisher | Informa UK Limited |
| Publisher Date | 2015-05-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: Journal of Receptor, Ligand and Channel Research Biochemistry and Molecular Biology Cardiac Hypertrophy |
| Content Type | Text |
