ATP and Sulfonylurea Linkage in the KATP Channel Solves a Diabetes Puzzler

At 30,000 feet, ATP-sensitive potassium (KATP) channels are seen coupling the metabolic status of the cell to its electrical excitability. But down at the molecular level of the β-cell, there is a lot more coupling going on in exactly how the KATP channel does this. Coupling is developed in the conceptual framework of linkage (1), which thermodynamically quantifies how conformational states of high and low affinity in regulatory ligand binding sites reciprocally link with additional sites, and active and inactive conformations of proteins. It is also at the heart of a molecular medicine puzzler with a satisfying solution originating from a study by Proks et al. (2) reported in this issue. The main gate of the KATP channel opens and shuts to regulate β-cell electrical excitability and insulin secretion. Only a small number of the channels need be open for outflow of potassium ions to keep the β-cell electrically at rest, thus preventing insulin secretion. In a high glucose setting, however, β-cell metabolism generates ATP at the expense of ADP, which effectively shuts all KATP channels to stop potassium ion outflow. This leads to activation of voltage-dependent calcium channels and calcium influx, which triggers secretory granule exocytosis mediating insulin secretion. Regulatory ligand binding sites link the main gate of the KATP channel to glucose metabolism via ATP, MgATP, and MgADP (3). The β-cell KATP channel is a hetero-octameric protein of four inner pore-forming Kir6.2 and four outer sulfonylurea receptor 1 (SUR1) subunits (Fig. 1). The gate is formed by concerted action of all four Kir6.2 subunits (4). Each Kir6.2 subunit also has an independent ATP site whose occupancy effectively can shut the gate and can keep it shut (5), referred to as inhibition. Pharmacological ligands also inhibit the KATP channel. Each SUR1 subunit …