| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Outline of Final Research Achievements |
Mechanisms of Ca release from SR/ER through the cardiac RyR2 w a point mutation K4750Q linked to ventricular tachycardia VT were functionally examined by measuring Ca signals and single RyR2 channel currents. The Ca signals were obtained from HEK293 and cardiac HL-1 cells expressing RyR channels. The single-channel currents were from RyR2 purified proteins. The mutation caused simultaneous functional defects in RyR2 function that include cytosolic Ca hyper-activation/sensitization, loss of cytosolic Ca/Mg-mediated inactivation, and luminal Ca hyper-activation/sensitization. The excessive SR Ca leak in K4750Q-expressing cells reduced [Ca]lum significantly lowering CPVT risk at rest. We thus show that the mutation markedly enhanced multiple RyR2 Ca regulatory mechanisms, which indicates that the K4750 residue resides at a pivotal structural point that synergizes cytosolic and luminal RyR2 control inputs.
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