1.A.110.1.1
OTOP1 of 600 aas and 12 TMSs in a 5 + 5 + 2 arrangement.  OTOP1 is a pH-sensitive proton-selective ion channel enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance (Tu et al. 2018). Two related murine genes, Otop2 and Otop3, and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology (Tu et al. 2018). Structural motifs for subtype-specific pH-sensitive gating of vertebrate otopetrin proton channels have been analyzed (Teng et al. 2022). Gating elements for carvacrol activation of the OTOP1 proton channel have been examined (Hu et al. 2024).  Carvacrol selectively activates mOTOP1, while mOTOP2, mOTOP3, and Chelonia mydas OTOP1 (CmOTOP1) are insensitive to carvacrol activation at neutral pH. Through chimera and point mutation experiments, swapping S134 in transmembrane segment 3 (TMS3) and T247 in the TM56 linker abolished carvacrol activation of mOTOP1 and conferred activation on CmOTOP1. Thus, these two residues are critical for carvacrol sensitivity. Thus, TMS3 and the TMS5-6 linker are pivotal gating residues of OTOP1 channels and potential docking sites for drug design (Hu et al. 2024).