Cardiac function depends on the highly regulated and co-ordinate activity of a large ensemble of potassium channels that control myocyte repolarization. While voltage-gated K⁺ channels have been well characterized in the heart, much less is known about regulation and/or targeting of two-pore K⁺ channel (K_2P) family members, despite their potential importance in modulation of heart function.

Here, we report a novel molecular pathway for membrane targeting of TREK-1, a mechano-sensitive K_2P channel regulated by environmental and physical factors including membrane stretch, pH, and polyunsaturated fatty acids (e.g. arachidonic acid). We demonstrate that β_IV-spectrin, an actin-associated protein, is co-localized with TREK-1 at the myocyte intercalated disc, associates with TREK-1 in the heart, and is required for TREK-1 membrane targeting. Mice expressing β_IV-spectrin lacking TREK-1 binding (qv^4J) display aberrant TREK-1 membrane localization, decreased TREK-1 activity, delayed action potential repolarization, and arrhythmia without apparent defects in localization/function of other cardiac potassium channel subunits. Finally, we report abnormal β_IV-spectrin levels in human heart failure.

These data provide new insight into membrane targeting of TREK-1 in the heart and establish a broader role for β_IV-spectrin in organizing functional membrane domains critical for normal heart function.