Insight into the therapeutic potential of ent-verticilide based on direct measures of RyR function

Pathological hyperactivity of cardiac ryanodine receptors (RyR2) can elevate cytosolic Ca2+ during diastole, which can contribute to diseases such as heart failure and arrhythmias. This makes the inhibition of RyR2, specifically in nanomolar (diastolic) Ca2+, a desirable effect for therapeutic agents. However, due to the important role of RyR2 in excitation-contraction coupling, the complete inhibition (channel blocking) or effects in micromolar (systolic) Ca2+ on RyR2 channel activity is a major concern.