A Non-Proton Ligand Sensor in the Acid-Sensing Ion Channel

Tian-Le Xu

Institute of Neuroscience and State Key Laboratory of Neuroscience, Chinese Academy of Sciences, Shanghai 200031, China

Acid-sensing ion channels (ASICs) have long been considered as extracellular proton (H+)-gated cation channels, and peripheral ASIC3 channels seem to be a natural sensor of acidic pain. Here we report the identification of a non-proton sensor on ASIC3. We show first that 2-guanidine-4-methylquinazoline (GMQ) causes persistent ASIC3 channel activation at the normal pH. Using GMQ as a probe and combining mutagenesis and covalent modification analysis, we then uncovered a novel ligand sensor lined by residues around E423 and E79 of the extracellular ‘palm’ domain of the ASIC3 channel that is crucial for activation by non-proton activators. Furthermore, we show that GMQ activates sensory neurons and causes pain-related behaviors in an ASIC3-dependent manner, indicating the functional significance of ASIC activation by non-proton ligands. Thus, natural ligands beyond protons may activate ASICs under physiological and pathological conditions through the non-proton ligand sensor, serving for channel activation independent of abrupt and marked acidosis.