A dual-targeted drug inhibits cardiac ryanodine receptor Ca²⁺ leak but activates SERCA2a Ca²⁺ uptake.

ABSTRACT: In the heart, genetic or acquired mishandling of diastolic [Ca²⁺] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca²⁺ release by drugs modulating RyR2 activity or increase in Ca²⁺ uptake by drugs modulating SR Ca²⁺ ATPase (SERCA2a) activity. Here, we combine these strategies by developing experimental compounds that act simultaneously on both processes. Our screening efforts identified the new 1,4-benzothiazepine derivative GM1869 as a promising compound. Consequently, we comparatively studied the effects of the known RyR2 modulators Dantrolene and S36 together with GM1869 on RyR2 and SERCA2a activity in cardiomyocytes from wild typ

SUBMITTER: Wegener JW 

PROVIDER: S-EPMC10681910 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature