The rodent vomeronasal organ (VNO) mediates the regulation of species-specific and interspecies social behaviors. We have used gene targeting to examine the role of the G protein Gαo, encoded by the gene Gnao1, in vomeronasal function. We used the Cre-loxP system to delete Gαo in those cells that express olfactory marker protein, which includes all vomeronasal sensory neurons of the basal layer of the VNO sensory epithelium. Using electrophysiology and calcium imaging, we show that the conditional null mice exhibit strikingly reduced sensory responses in V2R receptor-expressing vomeronasal sensory neurons to specific molecular cues, including MHC1 antigens, major urinary proteins, and exocrine gland-secreting peptide. Gαo is also vital for vomeronasal sensing of two Nformylated mitochondrially encoded peptides derived from NADH dehydrogenase 1. Furthermore, we show that Gαo is an essential requirement for the display of male-male territorial aggression as well as maternal aggression in mice. Finally, we show that Gαo-dependent maternal aggression can be induced by major urinary proteins. These cellular and behavioral phenotypes identify Gαo as the primary G-protein α-subunit mediating the detection of peptide and protein pheromones by sensory neurons of the VNO.formyl peptide receptor | olfaction | peptide detection | Trpc2 | social recognition T he mammalian olfactory system comprises a complex array of subsystems, but the functional significance of this organization remains unclear (1). The mouse vomeronasal organ (VNO)-which has attracted specific attention because of its vital role in social communication (2, 3)-consists of at least two distinct layers containing apical (superficial) and basal (deep) populations of vomeronasal sensory neurons (VSNs), which project their axons to discrete regions of the accessory olfactory bulb (AOB) (4-6). These VSN populations are characterized by differential expression of heterotrimeric G proteins and G proteincoupled receptors (GPCRs): apical VSNs express Gαi2 and members of the V1R family of vomeronasal GPCRs (7), whereas basal VSNs express Gαo and members of the V2R receptor family (8-10). VSNs of both layers express the transient receptor potential channel Trpc2 (11-13). Whether these two VNO subsystems function in relative isolation, each specialized to control a distinct subset of social behaviors, or whether they work in a cooperative and integrative manner remains unclear.A series of gene deletion studies has revealed an obligate requirement of Trpc2 (12-14) and at least some V1Rs (15, 16) and V2Rs (17, 18) for the generation of sensory responses in VSN populations. Together, these studies support a model of VSN signaling in which receptor occupancy, through G-protein coupling, causes activation of phospholipase C (PLC) that, in turn, leads to the activation of a Ca 2+ -permeable, Trpc2-dependent cation channel (19). Ca 2+ entry through this channel mediates both negative and positive VSN feedback regulation through calmodulin-dependent sensory adaptation and down...
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