Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium

Terrestrial vertebrates have evolved two anatomically and mechanistically distinct chemosensory structures: the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Although it has been generally thought that pheromones are detected through the VNO, whereas other chemicals are sensed by the MOE, recent evidence suggests that some pheromones may be detected through the MOE. Odorant receptors in the MOE are coupled to the type 3 adenylyl cyclase (AC3), an enzyme not expressed in the VNO. Consequently, odorants and pheromones do not elicit electrophysiological responses in the MOE of AC3(-/-) mice, although VNO function is intact. Here we report that AC3(-/-) mice cannot detect mouse milk, urine, or mouse pheromones. Inter-male aggressiveness and male sexual behaviors are absent in AC3(-/-) mice. Furthermore, adenylyl cyclase activity in membranes prepared from the MOE of wild-type mice, but not AC3(-/-) mice, is stimulated by 2-heptanone, a mouse pheromone. We conclude that signaling through AC3 in the MOE is obligatory for male sexual behavior, male-male aggressiveness, and the detection of some pheromones.