Acid-sensing ion channels are proton-activated ion channels expressed in the nervous system. They belong to the family of ENaC/Degenerins whose members share a conserved structure but are activated by widely diverse stimuli. We show that interaction of two aromatic residues, Tyr-72, located immediately after the first transmembrane segment, and Trp-288, located at the tip of a loop of the extracellular domain directed toward the first transmembrane segment, is essential for proton activation of the acid-sensing ion channels. The subdomain containing Trp-288 is a module tethered to the rest of the extracellular domain by short linkers and intrasubunit interactions between residues in the putative "proton sensor." Mutations in these two areas shift the apparent affinity of protons toward a more acidic range and change the kinetics of activation and desensitization. These results are consisting with displacement of the module relative to the rest of the extracellular domain to allow interaction of Trp-288 with Tyr-72 during gating. We propose that such interaction may provide functional coupling between the extracellular domain and the pore domain.