RT Journal Article
SR Electronic
T1 A dual-targeted drug inhibits cardiac ryanodine receptor Ca<sup>2+</sup> leak but activates SERCA2a Ca<sup>2+</sup> uptake
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302278
DO 10.26508/lsa.202302278
VO 7
IS 2
A1 Wegener, Jörg W
A1 Mitronova, Gyuzel Y
A1 ElShareif, Lina
A1 Quentin, Christine
A1 Belov, Vladimir
A1 Pochechueva, Tatiana
A1 Hasenfuss, Gerd
A1 Ackermann, Lutz
A1 Lehnart, Stephan E
YR 2024
UL https://www.life-science-alliance.org/content/7/2/e202302278.abstract
AB 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 type and arrhythmia-susceptible RyR2R2474S/+ mice by confocal live-cell imaging. All drugs reduced RyR2-mediated Ca2+ spark frequency but only GM1869 accelerated SERCA2a-mediated decay of Ca2+ transients in murine and human cardiomyocytes. Our data indicate that S36 and GM1869 are more suitable than dantrolene to directly modulate RyR2 activity, especially in RyR2R2474S/+ mice. Remarkably, GM1869 may represent a new dual-acting lead compound for maintenance of diastolic [Ca2+].