Large-scale high-throughput screen for cardiac ryanodine receptor targeted therapeutics.

ABSTRACT: In high-throughput screening (HTS) assays using fluorescence lifetime (FLT)-detected FRET, we have identified compounds that allosterically modulate the pathologically leaky ryanodine receptor (RyR) calcium release channels. These compounds may prevent or reduce the elevated Ca²⁺ that fuels arrhythmia, heart failure, and age-related neurodegeneration. RyRs are responsible for intracellular Ca²⁺ release from endoplasmic/sarcoplasmic reticulum (ER/SR). The resulting [Ca²⁺] pulse is a signal for many cellular processes, whereas sustained elevated [Ca²⁺] is pathologic. Our FRET-based HTS detects the pathology-linked RyR leaky state by monitoring binding of the accessory protein calmodulin and the DPc10 peptide (corresponding to RyR2 residues 2460-249

SUBMITTER: Nikolaienko R 

PROVIDER: S-EPMC12765055 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature