+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel



mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel



Journal of Receptor, Ligand and Channel Research 8: 43-51



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 059287104

Download citation: RISBibTeXText

PMID: 26312014

DOI: 10.2147/JRLCR.S78410


Related references

IL-6/STAT3 signaling in mice with dysfunctional type-2 ryanodine receptor. Jak-Stat 4(4): E1158379, 2015

Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules. American Journal of Physiology. Heart and Circulatory Physiology 300(6): H2187-H2195, 2011

Inhibition of CaMKII does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor. Plos One 9(8): E104338, 2015

Ryanodine sensitizes the cardiac Ca(2+) release channel (ryanodine receptor isoform 2) to Ca(2+) activation and dissociates as the channel is closed by Ca(2+) depletion. Proceedings of the National Academy of Sciences of the United States of America 98(24): 13625-13630, 2001

Beta-adrenergic signaling accelerates and synchronizes cardiac ryanodine receptor response to a single L-type Ca2+ channel. Proceedings of the National Academy of Sciences of the United States of America 106(42): 18028-18033, 2009

Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. Journal of Clinical Investigation 118(6): 2230-2245, 2008

Ryanodine sensitizes the cardiac ryanodine receptor to Ca2+ activation and dissociates as the channel is closed by Ca2+ depletion. Biophysical Journal 82(1 Part 2): 73a-74a, January, 2002

Insights into the gating mechanism of the ryanodine-modified human cardiac Ca2+-release channel (ryanodine receptor 2). Molecular Pharmacology 86(3): 318-329, 2014

Divergent effects of ruthenium red and ryanodine on Ca2+/calmodulin-dependent phosphorylation of the Ca2+ release channel (ryanodine receptor) in cardiac sarcoplasmic reticulum. Archives of Biochemistry and Biophysics 333(2): 368-376, 1996

Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95. Peerj 5: E4106, 2017

Single channel recordings of ryanodine receptor calcium release channel from cardiac sarcoplasmic reticulum. Japanese Circulation Journal 55(SUPPL A): 17, 1991

The predicted TM10 transmembrane sequence of the cardiac Ca2+ release channel (ryanodine receptor) is crucial for channel activation and gating. Journal of Biological Chemistry 279(5): 3635-3642, 2003

Bifenthrin causes transcriptomic alterations in mTOR and ryanodine receptor-dependent signaling and delayed hyperactivity in developing zebrafish (Danio rerio). Aquatic Toxicology 200: 50-61, 2018

Bifenthrin causes transcriptomic alterations in mTOR and ryanodine receptor-dependent signaling and delayed hyperactivity in developing zebrafish ( Danio rerio ). Aquatic Toxicology 200: 50-61, 2018

Evidence for negative charge in the conduction pathway of the cardiac ryanodine receptor channel provided by the interaction of K+ channel N-type inactivation peptides. Journal Of Membrane Biology. 163(3): 225-234, E 1, 1998