Mutations in a-kinase anchoring protein 9 disrupt β-adrenergic modulation of delayed rectifier potassium current in long QT syndrome.

Inherited long QT syndrome (LQTS) is a life-threatening cardiac channelopathy characterized by impaired ventricular repolarization and heightened susceptibility to ventricular arrhythmias and sudden cardiac death. While mutations in ion channel genes (e.g., KCNQ1, KCNH2) are well-known causes of LQTS, emerging evidence highlights the critical role of regulatory proteins, including a-kinase anchoring protein 9 (AKAP9), in modulating channel function. AKAP9 scaffolds protein kinase A (PKA), protein phosphatase 1 (PP1), and phosphodiesterase PDE4D3 into a macromolecular complex with KCNQ1, enabling dynamic phosphorylation of the potassium channels in response to β-adrenergic stimulation. Mutations in AKAP9 gene (e.g., S1570L) or its binding partner KCNQ1 (e.g., G589D) destabilize this complex, impairing PKA-mediated phosphorylation of KCNQ1 at serine-27. This defect blunts the sympathetic enhancement of slow delayed rectifier potassium channel (IKs), a critical mechanism for augmenting repolarization reserve during stress. Consequently, action potential duration prolongation, QT interval elongation, and early afterdepolarizations even polymorphic ventricular tachycardia were induced, particularly under conditions of heightened sympathetic tone. This review focuses on how AKAP9 mutations disrupt the sympathetic regulation of the IKs, mediated by the KCNQ1-KCNE1 channel complex, and contribute to the pathogenesis of LQTS type 11.