Ca²⁺–Calmodulin Feedback Mediates Sensory Adaptation and Inhibits Pheromone-Sensitive Ion Channels in the Vomeronasal Organ

Abstract

The mammalian vomeronasal organ (VNO) mediates the regulation of social behaviors by complex chemical signals. These cues trigger transient elevations of intracellular Ca(2+) in vomeronasal sensory neurons (VSNs), but the functional role of such Ca(2+) elevations is unknown. We show that stimulus-induced Ca(2+) entry plays an essential role as a negative feedback regulator of VSN sensitivity. Electrophysiological VSN responses undergo effective sensory adaptation that requires the influx of Ca(2+) and is mediated by calmodulin (CaM). Removal of the Ca(2+)-CaM feedback eliminates this form of adaptation. A key target of this feedback module is the pheromone-sensitive TRPC2-dependent cation channel of VSNs, as its activation is strongly inhibited by Ca(2+)-CaM. Our results reveal a previously unrecognized CaM-signaling pathway that endows the VSNs with a mechanism for adjusting gain and sensitivity of chemosensory signaling in the VNO.