Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels

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From worm to man, many odorant signals are perceived by the binding of volatile ligands to odorant receptors1 that belong to the G-protein-coupled receptor (GPCR) family2. They couple to heterotrimeric G-proteins, most of which induce cAMP production3. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of odorant signal transduction in insects, because their odorant receptors, which lack any sequence similarity to other GPCRs4, are composed of conventional odorant receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein5, such as Or83b in Drosophila6. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane4,7. However, G proteins are expressed in insect olfactory receptor neurons8, and olfactory perception is modified by mutations affecting the cAMP transduction pathway9. Here we show that application of odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca2+ concentration. Expression of Or83b alone leads to functional ion channels not directly responding to odorants, but being directly activated by intracellular cAMP or cGMP. Insect odorant receptors thus form ligand-gated channels as well as complexes of odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged odorant signalling.

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Figure 1: Co-expressed Or22a and Or83b mediate ethyl-butyrate-stimulated ion currents.
Figure 2: Odour signal transduction by means of G s protein signalling.
Figure 3: Cyclic nucleotides activate odorant receptors.
Figure 4: Modification of a putative Or83b pore region alters ion permeability.


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We thank S. Arend, S. Dietel, S. Kaltofen, A. Roßner and R. Stieber for technical assistance, E. Grosse-Wilde for discussion, E. Neuhaus and H. Hatt for providing the Or22a and Or83b DNA, and M. Biel for providing human HCN2 DNA. This study was supported by the Max Planck Society (D.W., M.C.S. and B.S.H.) and SFB 604 (TP 4, S.H.H.).

Author Contributions D.W. designed the experiments, performed the whole-cell patch-clamp and the calcium-imaging experiments, and analysed the data. R.B. and R.S. made the laser scanning recordings and contributed to the electrophysiological experiments. R.H. performed the cAMP radioreceptor assay. M.C.S. contributed to the bioinformatics and molecular biology effort. D.W. and S.H.H. wrote the paper. B.S.H. and M.C.S. contributed to the manuscript. All authors discussed the concepts and results, and commented on the manuscript.

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Correspondence to Dieter Wicher.

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Wicher, D., Schäfer, R., Bauernfeind, R. et al. Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature 452, 1007–1011 (2008) doi:10.1038/nature06861

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