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Updated: Apr 5, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel
Tai-Qin Huang1, Min-Xu Zou1, Daniel A Pasek1
1Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
Abstract:
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 Ryr2 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 Ryr2 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 Ryr2 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.
Insights
Dysfunctional cardiac ryanodine receptors (RyR2) in mice activate mTOR signaling, promoting cardiac hypertrophy. Inhibiting mTOR with rapamycin reduced heart size but did not extend lifespan.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- The cardiac ryanodine receptor ion channel (RyR2) is crucial for cardiac function.
- Mutations in RyR2 can lead to impaired calmodulin inhibition, cardiac hypertrophy, and premature death.
- The role of growth-promoting signaling pathways in RyR2-associated cardiac dysfunction is not fully understood.
Purpose of the Study:
- To investigate the involvement of the mTOR signaling pathway in the pathogenesis of cardiac hypertrophy in a mouse model with a dysfunctional RyR2.
- To determine the impact of mTOR inhibition on cardiac function and survival in these mice.
Main Methods:
- Generated a mouse model with specific mutations (ADA) in the calmodulin binding domain of RyR2.
- Assessed protein and phosphorylation levels of mTOR and its associated signaling molecules in wild-type and mutant mouse hearts.
- Administered rapamycin, an mTOR inhibitor, to wild-type and mutant mice and evaluated cardiac parameters and survival.
Main Results:
- Mutant RyR2 mice exhibited increased phosphorylation of mTOR and its downstream targets (p70S6K, S6, 4E-BP1), indicating enhanced mTOR activity.
- No significant increase in upstream mTOR kinases (PDK1, AKT, AMPK, ERK1/2) was observed.
- Rapamycin treatment reduced heart-to-body weight ratio and improved cardiac performance in mutant mice but did not prolong survival.
Conclusions:
- Dysfunctional RyR2 in mice is linked to altered mTOR signaling activity, contributing to cardiac growth and dysfunction.
- mTOR signaling plays a significant role in the development of cardiac hypertrophy associated with RyR2 mutations.
- Targeting mTOR may offer therapeutic potential for RyR2-related cardiac conditions, although it does not fully address the underlying pathology or extend lifespan.
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