Olfactory marker protein directly buffers cAMP to avoid depolarization-induced silencing of olfactory receptor neurons.

Olfactory receptor neurons (ORNs) use odour-induced intracellular cAMP surge to gate cyclic nucleotide-gated nonselective cation (CNG) channels in cilia. Prolonged exposure to cAMP causes calmodulin-dependent feedback-adaptation of CNG channels and attenuates neural responses. On the other hand, the odour-source searching behaviour requires ORNs to be sensitive to odours when approaching targets. How ORNs accommodate these conflicting aspects of cAMP responses remains unknown. Here, we discover that olfactory marker protein (OMP) is a major cAMP buffer that maintains the sensitivity of ORNs. Upon the application of sensory stimuli, OMP directly captured and swiftly reduced freely available cAMP, which transiently uncoupled downstream CNG channel activity and prevented persistent depolarization. Under repetitive stimulation, OMP-/- ORNs were immediately silenced after burst firing due to sustained depolarization and inactivated firing machinery. Consequently, OMP-/- mice showed serious impairment in odour-source searching tasks. Therefore, cAMP buffering by OMP maintains the resilient firing of ORNs.

Olfactory receptor neurons express olfactory marker protein but not calpain 5 from the same genomic locus.

Gene expression is highly regulated to functionally diversify cells. Genes that cooperate in the same physiological processes occasionally reside within nearby regions in a chromosome. Olfactory marker protein (OMP) is highly expressed in mature olfactory receptor neurons (ORNs), but its physiological roles are not fully understood. According to the genomic map, the OMP gene is located within an intron of the calcium-dependent protease, calpain 5 (CAPN5); in other words, the OMP gene is a nested intronic gene. Thus, we attempted to investigate the gene expression and protein distribution of CAPN5 in the olfactory epithelium compared with that in the central nervous system (CNS). By performing reverse-transcriptase PCR and in situ hybridization, we confirmed that CAPN5 mRNA was expressed in the olfactory epithelium. We then performed immunohistological investigations using sliced preparations obtained from mice expressing GFP under OMP promoter activity. The detected GFP fluorescence was restricted to the knob, soma and axon bundles of the ORNs, while CAPN5 immunoreactivity (CAPN5-IR) was ubiquitously detected in the olfactory epithelial layer and lamina propria; signals were strongly detected in the supporting cells within the epithelium. In the CNS, CAPN5 signals were widely detected and were especially strong in the hippocampal formation and the piriform cortex as previously indicated. Therefore, these data indicate that ORNs express OMP but not CAPN5 from CAPN5 gene expression even though they are localized in the same genomic locus. The mechanisms by which the OMP promoter is regulated require detailed investigations.