Disruption of local signaling domains occurs in LQT-1 syndrome. Stimulation of β-adrenergic receptors (β-ARs) in the heart leads to PKA-dependent phosphorylation of multiple intracellular targets in cardiac myocytes. These targets include the ryanodine receptor (RyR2), L-type calcium channels, and the KCNQ1/KCNE1 K⁺ channel. In response to stress in healthy patients, β-AR stimulation results in phosphorylation of all three of these targets and uniform electrical activity on the ECG (upper ECG). When the KCNQ1/KCNE1 complex is disrupted by an inherited mutation, an unbalanced cellular response occurs, which leads to dysfunctional rhythm (lower ECG). Modified with permission from ref. 27. SR, sarcoplasmic reticulum; VGCC, voltage-gated calcium channel.