Cnpy1 is a candidate endoplasmic reticulum chaperone of Vomeronasal type 2 GPCRs

Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express V1R or V2R G-protein coupled receptors (GPCRs), along with their respective Gαi2 or Gαo G-protein subunits. We have previously reported that Gαo-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture. Here we identify full-length mouse Cnpy1 with its expression and localization exclusive to the ER of Gαo neurons. Cnpy1 deletion resulted in mice that were deficient in Gαo neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male-male aggressive behavior. In Cnpy1 ^-/- mice, Gαo neuron develop normally till birth, but undergo selective, progressive apoptosis during postnatal development, despite normal trafficking of V2R GPCRs to dendritic tips. Immunoprecipitation and mass spectrometry revealed that Cnpy1 associates with V2R GPCRs and other ER chaperones. Together, these findings identify Cnpy1 as a component of an ER chaperone complex essential for Gαo neuron signaling and survival.