Voltage-Gated$\text{Na}_{\text{v}}$Channel Targeting in the Heart Requires an Ankyrin-G-Dependent Cellular Pathway

Voltage-gated$\text{Na}_{\text{v}}$channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart,$\text{Na}_{\text{v}}$1.5 is the predominant$\text{Na}_{\text{v}}$channel, and$\text{Na}_{\text{v}}$1.5-dependent activity regulates rapid upstroke of the cardiac action potential.$\text{Na}_{\text{v}}$1.5 activity requires precise localization at specialized cardiomyocyte membrane domains. However, the molecular mechanisms underlying$\text{Na}_{\text{v}}$channel trafficking in the heart are unknown. In this paper, we demonstrate that ankyrin-G is required for$\text{Na}_{\text{v}}$1.5 targeting in the heart. Cardiomyocytes with reduced ankyrin-G display reduced$\text{Na}_{\text{v}}$1.5 expression, abnormal$\text{Na}_{\text{v}}$1.5 membrane targeting, and reduced Na⁺ channel current density. We define the structural requirements on ankyrin-G for$\text{Na}_{\text{v}}$1.5 interactions and demonstrate that loss of$\text{Na}_{\text{v}}$1.5 targeting is caused by the loss of direct$\text{Na}_{\text{v}}$1.5--ankyrin-G interaction. These data are the first report of a cellular pathway required for$\text{Na}_{\text{v}}$channel trafficking in the heart and suggest that ankyrin-G is critical for cardiac depolarization and$\text{Na}_{\text{v}}$channel organization in multiple excitable tissues.