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

A t 30,000 feet, ATP-sensitive potassium (KATP)channels are seen coupling the metabolic statusof the cell to its electrical excitability. But downat the molecular level of the b-cell, there is a lot more coupling going on in exactly how the KATP channel does this. Coupling is developed in the conceptual frame-work of linkage (1), which thermodynamically quantifies how conformational states of high and low affinity in reg-ulatory 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 b-cell electrical excitability and insulin secretion. Only a small number of the channels need be open for outflow of potassium ions to keep the b-cell electrically at rest, thus preventing insulin secretion. In a high glucose