Schematic depicting excitation−contraction coupling and the mechanism of HNO action. The main HNO targets in cardiac myocytes are shown as well as the proposed mechanism by which HNO modifies SERCA2a/PLN interaction. Upon membrane depolarization, Ca²⁺ (yellow spheres) enters the cell through L-type Ca²⁺ channels (LTCC) and activates the RYR2 of the SR to produce further Ca²⁺ release. Ca²⁺ binds to the myofilaments (MF) to produce contraction. Most of the Ca²⁺ is then reuptaken by SERCA2a, and a small fraction is extruded from the cell through NCX. HNO activates RYR2 and SR Ca²⁺ release, SR Ca²⁺ uptake, and MF Ca²⁺ sensitivity, without significantly affecting LTCC and NCX. The inset of the figure shows the mechanism proposed by Keceli et al. (2019) by which HNO modifies thiol groups in PLN. It is suggested that when the HNO/thiol stoichiometry approaches a 1:1 ratio, similar to that anticipated in vivo under normal physiological conditions, an intramolecular disulfide bond between two cysteines of the transmembrane domain of PLN is formed, relieving the preexisting SERCA2a inhibition.