title: Activation state of the M3 muscarinic acetylcholine receptor modulates mammalian odorant receptor signaling.
abstract: A diverse repertoire of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) enables cells to sense their environment. Mammalian olfaction requires the activation of odorant receptors (ORs), the largest family of GPCRs; however, whether ORs functionally interact with other families of GPCRs is unclear. We show that the interaction of ORs with the type 3 muscarinic acetylcholine receptor (M3-R), which is found in olfactory sensory neurons (OSNs), modulated OR responses to cognate odorants. In human embryonic kidney-293T cells, ORs and the M3-R physically interacted, and the M3-R increased the potency and efficacy of odorant-elicited responses of several ORs. Selective M3-R antagonists attenuated odorant-dependent activation of OSNs, and, when the M3-R and ORs were expressed in transfected cells, OR activation was enhanced by muscarinic agonists and inhibited by muscarinic antagonists. Furthermore, M3-R-dependent potentiation of OR signaling synergized with that of receptor transporting protein 1S (RTP1S), an accessory factor required for the efficient membrane targeting of ORs. However, the M3-R did not enhance the abundance of ORs at the cell surface, suggesting that the M3-R acted through a distinct mechanism independent of RTP1S. Finally, the activation of ORs by cognate odorants transactivated the M3-R in the absence of its agonist. The crosstalk between ORs and the M3-R suggests that the functional coupling of ORs and the M3-R is required for robust OR activation.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Yun Rose
authors.initials: YR
authors.lastname: Li
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsunami
mesh_terms: D001285:Atropine / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018034:Olfactory Receptor Neurons / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D001572:Benzofurans; D018679:Cholinergic Agonists; D007476:Ionophores; D026901:Membrane Transport Proteins; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; C495316:RTP1 protein, human; D043587:Receptor, Muscarinic M3; D043562:Receptors, G-Protein-Coupled; D018035:Receptors, Odorant; D005576:Colforsin; D015759:Ionomycin; D001285:Atropine; D002217:Carbachol; C101207:darifenacin; D000242:Cyclic AMP