Inhibitory Odorant Signaling in Mammalian Olfactory Receptor Neurons

1 Whitney Laboratory, Center for Smell and Taste, and McKnight Brain Institute, and 2 Departments of Biology and Neuroscience, University of Florida, Gainesville, Florida Submitted 6 November 2009; accepted in final form 17 December 2009 ABSTRACT Odorants inhibit as well as excite olfactory receptor neurons (ORNs) in many species of animals. Cyclic nucleotide-dependent activation of canonical mammalian ORNs is well established but it is still unclear how odorants inhibit these cells. Here we further implicate phosphoinositide-3-kinase (PI3K), an indispensable element of PI signaling in many cellular processes, in olfactory transduction in rodent ORNs. We show that odorants rapidly and transiently activate PI3K in the olfactory cilia and in the olfactory epithelium in vitro. We implicate known G-protein–coupled isoforms of PI3K and show that they modulate not only the magnitude but also the onset kinetics of the electrophysiological response of ORNs to complex odorants. Finally, we show that the ability of a single odorant to inhibit another can be PI3K dependent. Our collective results provide compelling support for the idea that PI3K-dependent signaling mediates inhibitory odorant input to mammalian ORNs and at least in part contributes to the mixture suppression typically seen in the response of ORNs to complex natural odorants. Address for reprint requests and other correspondence: K. Ukhanov, Center for Smell and Taste, PO Box 100127, University of Florida, Gainesville, FL 32610-0127 (E-mail: ukhanov{at}mbi.ufl.edu ).