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Cell. 2016 Jun 16;165(7):1734-1748. doi: 10.1016/j.cell.2016.05.001. Epub 2016 May 26.

A Family of non-GPCR Chemosensors Defines an Alternative Logic for Mammalian Olfaction.

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Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Departments of Molecular and Cellular Biology and Organismic and Evolutionary Biology, Center for Brain Science, Harvard University, Howard Hughes Medical Institute, Cambridge, MA 02138, USA.
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:


Odor perception in mammals is mediated by parallel sensory pathways that convey distinct information about the olfactory world. Multiple olfactory subsystems express characteristic seven-transmembrane G-protein-coupled receptors (GPCRs) in a one-receptor-per-neuron pattern that facilitates odor discrimination. Sensory neurons of the "necklace" subsystem are nestled within the recesses of the olfactory epithelium and detect diverse odorants; however, they do not express known GPCR odor receptors. Here, we report that members of the four-pass transmembrane MS4A protein family are chemosensors expressed within necklace sensory neurons. These receptors localize to sensory endings and confer responses to ethologically relevant ligands, including pheromones and fatty acids, in vitro and in vivo. Individual necklace neurons co-express many MS4A proteins and are activated by multiple MS4A ligands; this pooling of information suggests that the necklace is organized more like subsystems for taste than for smell. The MS4As therefore define a distinct mechanism and functional logic for mammalian olfaction.

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