Inverse agonist-like action of cadmium on G-protein-gated inward-rectifier K+ channels

Highlights: → We examined allosteric control of K+ channel gating. → We identified a high-affinity site for Cd2+ to inhibit Kir3.2 activity. → The 6-coordination geometry supports the binding. → Cd2+ inhibits Kir3.2 by trapping the conformation in the closed state. -- Abstract: The gate at the pore-forming domain of potassium channels is allosterically controlled by a stimulus-sensing domain. Using Cd2+ as a probe, we examined the structural elements responsible for gating in an inward-rectifier K+ channel (Kir3.2). One of four endogenous cysteines facing the cytoplasm contributes to a high-affinity site for inhibition by internal Cd2+. Crystal structure of its cytoplasmic domain in complex with Cd2+ reveals that octahedral coordination geometry supports the high-affinity binding. This mode of action causes the tethering of the N-terminus to CD loop in the stimulus-sensing domain, suggesting that their conformational changes participate in gating and Cd2+ inhibits Kir3.2 by trapping the conformation in the closed state like 'inverse agonist'.