Subcellular trafficking and endocytic recycling of K_ATP channels

Sarcolemmal/plasmalemmal ATP-sensitive K⁺ (K_ATP) channels have key roles in many cell types and tissues. Hundreds of studies have described how the K_ATP channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic b-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility. It is increasingly becoming apparent, however, that K_ATP channels are regulated beyond changes in their activity. Recent studies have highlighted that K_ATP channel surface expression is a tightly regulated process with similar implications in health and disease. The surface expression of K_ATP channels is finely balanced by several trafficking steps including synthesis, assembly, anterograde trafficking, membrane anchoring, endocytosis, endocytic recycling, and degradation. This review aims to summarize the physiological and pathophysiological implications of K_ATP channel trafficking and mechanisms that regulate K_ATP channel trafficking. A better understanding of this topic has potential to identify new approaches to develop therapeutically useful drugs to treat K_ATP channel-related diseases.