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1.A.69 The Heteromeric Odorant Receptor Channel (HORC) Family

In insects, each olfactory sensory neuron expresses between one and three ligand-binding members of the olfactory receptor (OR) gene family, along with the highly conserved and broadly expressed Or83b co-receptor. The functional insect OR consists of a heteromeric complex of unknown stoichiometry but comprising at least one variable odorant-binding subunit and one constant Or83b family subunit. Insect ORs lack homology to G-protein-coupled chemosensory receptors in vertebrates and possess a distinct seven-transmembrane topology with the amino terminus located intracellularly. Sato et al. (2008) and Touhara (2009) showed that heteromeric insect ORs comprise a new class of ligand-activated non-selective cation channels. Heterologous cells expressing silkmoth, fruitfly or mosquito heteromeric OR complexes show extracellular Ca2+ influx and cation-non-selective ion conductance on stimulation with odorant or pheromone. Odour-evoked OR currents are independent of known G-protein-coupled second messenger pathways. The fast response kinetics and OR-subunit-dependent K+ ion selectivity of the insect OR complex support the hypothesis that the complex between OR and Or83b itself confers channel activity. The ligand (odorant)-gated ion channels formed by an insect OR complex seem to be the basis for a unique strategy that insects have acquired to respond to the olfactory environment (Sato et al., 2008).

Insect odorant receptors are composed of conventional odorant receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein, such as Or83b in Drosophila. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane. However, G proteins are expressed in insect olfactory receptor neurons, and olfactory perception is modified by mutations affecting the cAMP transduction pathway. Application of odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of ionotropic and metabolotropic pathways, and a subsequent increase in the intracellular Ca2+ concentration (Wicher et al., 2008). 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. They, thereby, provide rapid and transient as well as sensitive and prolonged odorant signalling (Wicher et al., 2008).

ORs have been identified from four insect orders (Coleoptera, Lepidoptera, Diptera, and Hymenoptera). Although all ORs share the same G-protein coupled receptor structure with seven transmembrane domains, they present poor sequence homologies within and between species. D. melanogaster is the only insect species where Ors have been extensively studied from expression pattern establishment to functional investigations (Jacquin-Joly and Merlin, 2004). One OR type is selectively expressed in a subtype of olfactory receptor neurons, and one olfactory neuron expresses only one type of OR. In addition, all olfactory neurons expressing one OR type converge to the same glomerulus in the antennal lobe. The olfactory mechanism, thus, appears to be conserved between insects and vertebrates (Jacquin-Joly and Merlin, 2004).

After the discovery of the complete repertoire of D. melanogaster Olfactory Receptors (ORs), candidate ORs have been identified from at least 12 insect species from four orders (Coleoptera, Lepidoptera, Diptera, and Hymenoptera). Although all ORs share the same G-protein coupled receptor structure with seven TMSs, they share poor sequence identity. One OR type is selectively expressed in a subtype of olfactory receptor neurons, and one olfactory neuron expresses only one type of OR. The olfactory mechanism, further, appears to be conserved between insects and vertebrates. The C-terminal region (TMSs4-7) of OR83b is involved in homodimer and heterodimer formation (with OR22a) which suggests why the C-termini of insect ORs are highly conserved. There may be two possible ion channel pathways, one formed by the TMS4-5 region with the intracellular pore-forming domain and the other formed by TM5-6 with the extracellular pore forming domain. Odorant receptors generally comprise the obligate co-receptor, Orco, and one of a family of highly divergent odorant 'tuning' receptors. The two subunits are thought to come together at some as-yet unknown stoichiometry to form a functional complex that is capable of both ionotropic and metabotropic signalling. Segments and residues involved in this interaction have been identified (Carraher et al. 2015).

The generalized reaction catalyzed by HORC is:

cations (in) cations (out)

References associated with 1.A.69 family:

Carraher C., Dalziel J., Jordan MD., Christie DL., Newcomb RD. and Kralicek AV. (2015). Towards an understanding of the structural basis for insect olfaction by odorant receptors. Insect Biochem Mol Biol. 66:31-41. 26416146
Carraher, C., A. Authier, B. Steinwender, and R.D. Newcomb. (2012). Sequence Comparisons of Odorant Receptors among Tortricid Moths Reveal Different Rates of Molecular Evolution among Family Members. PLoS One 7: e38391. 22701634
Carraher, C., A.R. Nazmi, R.D. Newcomb, and A. Kralicek. (2013). Recombinant expression, detergent solubilisation and purification of insect odorant receptor subunits. Protein Expr Purif 90: 160-169. 23770557
Harini, K. and R. Sowdhamini. (2012). Molecular Modelling of Oligomeric States of DmOR83b, an Olfactory Receptor in D. Melanogaster. Bioinform Biol Insights 6: 33-47. 22493562
Jacquin-Joly, E. and C. Merlin. (2004). Insect olfactory receptors: contributions of molecular biology to chemical ecology. J Chem Ecol 30: 2359-2397. 15724962
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Miura, N., T. Nakagawa, K. Touhara, and Y. Ishikawa. (2010). Broadly and narrowly tuned odorant receptors are involved in female sex pheromone reception in Ostrinia moths. Insect Biochem Mol Biol 40: 64-73. 20044000
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Mukunda, L., S. Lavista-Llanos, B.S. Hansson, and D. Wicher. (2014). Dimerisation of the Drosophila odorant coreceptor Orco. Front Cell Neurosci 8: 261. 25221476
Nakagawa, T., M. Pellegrino, K. Sato, L.B. Vosshall, and K. Touhara. (2012). Amino acid residues contributing to function of the heteromeric insect olfactory receptor complex. PLoS One 7: e32372. 22403649
Nichols, A.S. and C.W. Luetje. (2010). Transmembrane segment 3 of Drosophila melanogaster odorant receptor subunit 85b contributes to ligand-receptor interactions. J. Biol. Chem. 285: 11854-11862. 20147286
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Sato, K., K. Tanaka, and K. Touhara. (2011). Sugar-regulated cation channel formed by an insect gustatory receptor. Proc. Natl. Acad. Sci. USA 108: 11680-11685. 21709218
Sato, K., M. Pellegrino, T. Nakagawa, T. Nakagawa, L.B. Vosshall, and K. Touhara. (2008). Insect olfactory receptors are heteromeric ligand-gated ion channels. Nature. 452: 1002-1006. 18408712
Stensmyr, M.C., H.K. Dweck, A. Farhan, I. Ibba, A. Strutz, L. Mukunda, J. Linz, V. Grabe, K. Steck, S. Lavista-Llanos, D. Wicher, S. Sachse, M. Knaden, P.G. Becher, Y. Seki, and B.S. Hansson. (2012). A conserved dedicated olfactory circuit for detecting harmful microbes in Drosophila. Cell 151: 1345-1357. 23217715
Touhara, K. (2009). Insect olfactory receptor complex functions as a ligand-gated ionotropic channel. Ann. N.Y. Acad. Sci. 1170: 177-180. 19686133
Wicher, D., R. Schäfer, R. Bauernfeind, M.C. Stensmyr, R. Heller, S.H. Heinemann, and B.S. Hansson. (2008). Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature. 452: 1007-1011. 18408711