Acids can disturb the ecosystem of wild animals through altering their olfaction and olfaction-related survival behaviors. It is known that the main olfactory epithelia (MOE) of mammals rely on odorant receptors and type III adenylyl cyclase (AC3) to detect general odorants. However, it is unknown how the olfactory system sense protons or acidic odorants. Here, we show that while the MOE of AC3 knockout (KO) mice failed to respond to an odor mix in electro-olfactogram (EOG) recordings, it retained a small fraction of acid-evoked EOG responses. The acetic acid-induced EOG responses in wild-type (WT) MOE can be dissected into two components: the big component dependent on the AC3-mediated cAMP pathway and the much smaller component not. The small acid-evoked EOG response of the AC3 KOs was blocked by diminazene, an inhibitor of acid-sensing ion channels (ASICs), but not by forskolin/IBMX that desensitize the cAMP pathway. AC3 KO mice lost their sensitivity to detect pungent odorants but maintained sniffing behavior to acetic acid. Immunofluorescence staining demonstrated that ASIC1 proteins were highly expressed in olfactory sensory neurons (OSNs), mostly enriched in the knobs, dendrites, and somata, but not in olfactory cilia. Real-time polymerase chain reaction further detected the mRNA expression of ASIC1a, ASIC2b, and ASIC3 in the MOE. Additionally, mice exhibited reduced preference to attractive objects when placed in an environment with acidic volatiles. Together, we conclude that the mouse olfactory system has a non-conventional, likely ASIC-mediated ionotropic mechanism for acid sensing.
