According to Marks and colleagues, catecholamines control excitation-contraction coupling gain not only at the level of LTCCs and PLB, but also at the level of RyR2 by phosphorylating it at S2808. The latter reduces RyR2 affinity for the stabilizing accessory protein, FKBP12.6, and increases its open probability. In heart failure, sustained catecholamine stimulation leads to hyperphosphorylation, leaky RyR2, spontaneous Ca²⁺ release and, via NCX, spontaneous depolarizations. The new data presented in this issue of the JCI (25, 26) now suggest that phosphorylation at S2808 alone does not suffice to dissociate FKBP12.6 but that it needs oxidation of the channel plus phosphorylation. The level of oxidizing ROS is commonly increased in heart failure and, importantly, the increased Ca²⁺ leak from RyR2 (in consequence of oxidation and phosphorylation) further increases ROS production, e.g., from mitochondria. This constitutes a classical vicious circle. Black arrows and lettering indicate basic excitation-contraction coupling; red arrows indicate changes under chronic catecholamine stimulation and heart failure. The red dotted line indicates Ca²⁺ leak. Adapted with permission from Nature (35).