Conductance of P2X4 purinergic receptor is determined by conformational equilibrium in the transmembrane region

Partial agonists of ligand-gated ion channels reportedly offer clinical advantages over antagonists and full agonists in antidepressant and smoking-cessation treatment. In the cases of P2X purinergic receptors, the currents evoked by α,β-methylene ATP are lower than the currents evoked by ATP. Here, our NMR analyses revealed that the transmembrane region and the membrane side of the lower body exist in conformational equilibrium between the closed and open conformations, with slower exchange rates than the chemical shift difference (<100 s^-1), and that the small population of the open conformation of zebrafish P2X₄ purinergic receptor causes the partial activation in the α,β-methylene ATP-bound state. These findings provide insights into the mechanism underlying the partial activation of P2X₄ receptors and other ligand-gated ion channels.