Synapse
⌘+K
Synapse
PulseExploreClubsResearchersJournals
Instagram
HomeClubsExplore
July 8, 2026CirculationOpen Access

Dantrolene stops exercise-induced VT in RyR2 S2246L mutants by correcting erroneous Ca2+ channel activation.

View Full Paper
Ask AI
Bookmark
Share

Population

Knockin mouse model expressing the human catecholaminergic polymorphic ventricular tachycardia-associated…

Comparison

Dantrolene vs Wild-type mice/cardiomyocytes and untreated…

Design

Preclinical

Key result

The S2246L mutation in RyR2 causes defective interdomain interactions leading to erroneous Ca2+ channel activation and exercise-induced ventricular tachycardia, which was stopped by dantrolene.

Authors

TSTakeshi SuetomiMYMasafumi YanoHUHitoshi Uchinoumi

Discussion

Loading...

Member takes

Overview

Dantrolene suppressed VT in S2246L mice; hypothesis-generating for CPVT therapy, should not yet change practice.

Key Points

  • This research aims to elucidate how single amino acid mutations in the ryanodine receptor lead to catecholaminergic polymorphic ventricular tachycardia.
  • Utilized a knockin mouse model expressing the RyR2 S2246L mutant.
  • Examined Ca²⁺ spark frequency in saponin-permeabilized cardiomyocytes post-exercise.
  • Conducted binding assays with DP2246 to investigate interdomain interactions.
  • All knockin mice exhibited exercise-induced ventricular tachycardia.
  • Increased frequency of Ca²⁺ sparks observed in knockin cardiomyocytes (p<0.05).
  • Dantrolene administration corrected abnormal domain interactions and halted tachycardia.

Structured PICO

P
Population
Knockin mouse model expressing the human catecholaminergic polymorphic ventricular tachycardia-associated RyR2 mutant (S2246L) and saponin-permeabilized cardiomyocytes
E
Exposure
Dantrolene
C
Comparator
Wild-type mice/cardiomyocytes and untreated mutant mice
O
Outcome
Conformational defects of RyR2, Ca2+ spark frequency, and exercise-induced ventricular tachycardiasurrogate

The S2246L mutation in RyR2 causes CPVT through defective interdomain interactions that lead to aberrant diastolic Ca2+ release, a mechanism that can be reversed by dantrolene.

Cite This Study

Suetomi et al. (2011) studied Catecholaminergic polymorphic ventricular tachycardia. S2246L mutation in RyR2 vs. Wild-type was evaluated on Ventricular tachycardia after exercise and Ca2+ spark frequency. The S2246L mutation in RyR2 causes defective interdomain interactions leading to erroneous Ca2+ channel activation and exercise-induced ventricular tachycardia, which was stopped by dantrolene.

synapsesocial.com/papers/6a4e6a6ffc68164f0b3a4fd1https://doi.org/10.1161/circulationaha.111.023259
View Full Paper
Ask AI
Bookmark
Share