title: mTOR signaling in mice with dysfunctional cardiac ryanodine receptor ion channel.
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 ofRyr2ADA/ADAmice. 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 andRyr2ADA/ADAmice. 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-oldRyr2ADA/ADAmice 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.
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors: Tai-Qin
authors: TQ
authors: Huang
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors: Min-Xu
authors: MX
authors: Zou
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors: Daniel A
authors: DA
authors: Pasek
authors: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
authors: Gerhard
authors: G
authors: Meissner
keywords: RyR2; calmodulin; cardiac hypertrophy; rapamycin