Dual role of K_ATP channel C-terminal motif in membrane targeting and metabolic regulation

The coordinated sorting of ion channels to specific plasma membrane domains is necessary for excitable cell physiology. K_ATP channels, assembled from pore-forming (Kir6.x) and regulatory sulfonylurea receptor subunits, are critical electrical transducers of the metabolic state of excitable tissues, including skeletal and smooth muscle, heart, brain, kidney, and pancreas. Here we show that the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells. Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB). Moreover, we demonstrate that this Kir6.2 C-terminal AnkB-binding motif (ABM) serves a dual role in K_ATP channel trafficking and membrane metabolic regulation and dysfunction in these pathways results in human excitable cell disease. Thus, the K_ATP channel ABM serves as a previously unrecognized bifunctional touch-point for grading K _ATP channel gating and membrane targeting and may play a fundamental role in controlling excitable cell metabolic regulation.