Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization

Kato, Aya; Touhara, Kazushige

doi:10.1007/s00018-009-0111-6

Cited by 91 publications

(75 citation statements)

References 117 publications

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“…Early ideas suggested a key/lock type mechanism between the odorant and the OR protein [18,19], and much research has been performed during the past 50 years to describe the interactions of these odotopes with particular sites of the OR molecules. Our understanding of these interactions has far progressed from the early notion that the overall three-dimensional shape of the odorant molecule 'unlocks' the odorant receptor, thus giving rise to a conformational change which triggers the second messenger cascades, but a cohesive and predictive theory of these interactions is still missing (reviewed by [20]). …”

Section: Introductionmentioning

confidence: 99%

Honeybees (Apis mellifera) learn to discriminate the smell of organic compounds from their respective deuterated isotopomers

et al. 2014

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The understanding of physiological and molecular processes underlying the sense of smell has made considerable progress during the past three decades, revealing the cascade of molecular steps that lead to the activation of olfactory receptor (OR) neurons. However, the mode of primary interaction of odorant molecules with the OR proteins within the sensory cells is still enigmatic. Two different concepts try to explain these interactions: the 'odotope hypothesis' suggests that OR proteins recognize structural aspects of the odorant molecule, whereas the 'vibration hypothesis' proposes that intra-molecular vibrations are the basis for the recognition of the odorant by the receptor protein. The vibration hypothesis predicts that OR proteins should be able to discriminate compounds containing deuterium from their common counterparts which contain hydrogen instead of deuterium. This study tests this prediction in honeybees (Apis mellifera) using the proboscis extension reflex learning in a differential conditioning paradigm. Rewarding one odour (e.g. a deuterated compound) with sucrose and not rewarding the respective analogue (e.g. hydrogen-based odorant) shows that honeybees readily learn to discriminate hydrogen-based odorants from their deuterated counterparts and supports the idea that intra-molecular vibrations may contribute to odour discrimination.

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Section: Introductionmentioning

confidence: 99%

Honeybees (Apis mellifera) learn to discriminate the smell of organic compounds from their respective deuterated isotopomers

et al. 2014

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“…G protein-coupled receptors (GPCRs) comprise a large family of transmembrane signaling proteins that directly bind and transduce a range of cues including photons, odorants, neurotransmitters, and peptides (Pierce et al 2002;Kato and Touhara 2009;Demaria and Ngai 2010;Sung and Chuang 2010;Chamero et al 2012;Frooninckx et al 2012;Montell 2012;Bathgate et al 2013). Regulation of GPCR function, including regulation of membrane targeting and trafficking to specific subcellular regions, is a major contributor to the tuning of signaling efficacy and fidelity (e.g., Deretic et al 1995; type, closely related members of a GPCR family can be differentially targeted to different cell compartment membranes.…”

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confidence: 99%

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Brear

Yoon

Wojtyniak³

et al. 2014

Genetics

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The localization of signaling molecules such as G protein-coupled receptors (GPCRs) to primary cilia is essential for correct signal transduction. Detailed studies over the past decade have begun to elucidate the diverse sequences and trafficking mechanisms that sort and transport GPCRs to the ciliary compartment. However, a systematic analysis of the pathways required for ciliary targeting of multiple GPCRs in different cell types in vivo has not been reported. Here we describe the sequences and proteins required to localize GPCRs to the cilia of the AWB and ASK sensory neuron types in Caenorhabditis elegans. We find that GPCRs expressed in AWB or ASK utilize conserved and novel sequences for ciliary localization, and that the requirement for a ciliary targeting sequence in a given GPCR is different in different neuron types. Consistent with the presence of multiple ciliary targeting sequences, we identify diverse proteins required for ciliary localization of individual GPCRs in AWB and ASK. In particular, we show that the TUB-1 Tubby protein is required for ciliary localization of a subset of GPCRs, implying that defects in GPCR localization may be causal to the metabolic phenotypes of tub-1 mutants. Together, our results describe a remarkable complexity of mechanisms that act in a protein-and cellspecific manner to localize GPCRs to cilia, and suggest that this diversity allows for precise regulation of GPCR-mediated signaling as a function of external and internal context. SIGNALING molecules must be precisely localized to specific subcellular domains to optimize detection and transduction of external stimuli. G protein-coupled receptors (GPCRs) comprise a large family of transmembrane signaling proteins that directly bind and transduce a range of cues including photons, odorants, neurotransmitters, and peptides (Pierce et al. 2002;Kato and Touhara 2009;Demaria and Ngai 2010;Sung and Chuang 2010;Chamero et al. 2012;Frooninckx et al. 2012;Montell 2012;Bathgate et al. 2013). Regulation of GPCR function, including regulation of membrane targeting and trafficking to specific subcellular regions, is a major contributor to the tuning of signaling efficacy and fidelity (e.g., Deretic et al. 1995;Ango et al. 2000;Xia et al. 2003;Esseltine et al. 2012;. However, much remains to be understood regarding the mechanisms by which GPCR trafficking and membrane localization are regulated.GPCR-mediated signal transduction in many cellular contexts requires these proteins to be localized to specialized microtubule-based primary cilia. For example, in photoreceptors and olfactory neurons, efficient sensory signal transduction is mediated via localization of rhodopsin and olfactory receptors, together with other signaling molecules, to photoreceptor outer segments and olfactory neuron cilia, respectively (Insinna and Besharse 2008;Berbari et al. 2009;Pifferi et al. 2010;Deretic and Wang 2012). Receptors in the Hedgehog (Hh) morphogen signaling pathway such as the Smoothened and Patched transmembrane proteins, and the G...

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“…The canonical mechanism of olfactory transduction in the main olfactory epithelium is now quite well understood (2)(3)(4)(5). Odorant receptors (ORs) on ORN cilia are G protein-coupled-receptors (6) that, upon binding specific odorants, activate the adenylyl cyclase type-III via the G protein, G olf .…”

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confidence: 99%

Signaling by olfactory receptor neurons near threshold

Bhandawat

Reisert

Yau

2010

Proc. Natl. Acad. Sci. U.S.A.

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An important contributing factor for the high sensitivity of sensory systems is the exquisite sensitivity of the sensory receptor cells. We report here the signaling threshold of the olfactory receptor neuron (ORN). We first obtained a best estimate of the size of the physiological electrical response successfully triggered by a single odorantbinding event on a frog ORN, which was ∼0.034 pA and had an associated transduction domain spanning only a tiny fraction of the length of an ORN cilium. We also estimated the receptor-current threshold for an ORN to fire action potentials in response to an odorant pulse, which was ∼1.2 pA. Thus, it takes about 35 odorantbinding events successfully triggering transduction during a brief odorant pulse in order for an ORN to signal to the brain.olfaction | olfactory transduction | sensory transduction O ur visual system has pushed to the physical limit of sensitivity. Thus, a dark-adapted human subject can report light when just a few photons are absorbed in a retinal area spanning hundreds of rod photoreceptors, suggesting that each dark-adapted rod can signal the absorption of a single photon (1). What about the olfactory system? How many odorant molecules have to bind to an olfactory receptor neuron (ORN) to trigger an output signal? Retinal rods lack axons, so a graded, light-induced change in membrane potential directly modulates synaptic transmission. In contrast, ORNs have axons and require action potentials to convey olfactory signals to the brain. Hence, the question becomes: How many odorant-binding events successfully triggering transduction are required for changing an ORN's firing?The canonical mechanism of olfactory transduction in the main olfactory epithelium is now quite well understood (2-5). Odorant receptors (ORs) on ORN cilia are G protein-coupled-receptors (6) that, upon binding specific odorants, activate the adenylyl cyclase type-III via the G protein, G olf . The ensuing rise in cAMP opens a cyclic-nucleotide-gated (CNG), nonselective cation channel to produce a membrane depolarization. Additionally, the Ca 2+ influx through the CNG channels opens a Ca 2+ -activated Cl channel on the ciliary membrane (7,8). The resulting Cl − flux is, however, outward (i.e., inward Cl current) because of a high intracellular Cl − concentration maintained by steady Cl − uptake via a Na/K/Cl cotransporter, NKCC1 (9-12, but see 13), thus further depolarizing the cell to provide amplification (9, 10). Simultaneously, the Ca 2+ influx triggers, via Ca 2+ -calmodulin, multiple negative-feedback pathways that lead to adaptation (2-5). Finally, action-potential generation in ORNs involves voltage-gated Na channels and lowvoltage-activated (T-type) Ca channels, at least near threshold (14). Previously, we have found surprisingly that most odorant-binding events on an ORN are actually "inconsequential": that is, unsuccessful in triggering transduction, apparently because the odorant-OR complex typically exists too briefly to activate the downstream pathway (15). The events descr...

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Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization

Cited by 91 publications

References 117 publications

Honeybees (Apis mellifera) learn to discriminate the smell of organic compounds from their respective deuterated isotopomers

Honeybees (Apis mellifera) learn to discriminate the smell of organic compounds from their respective deuterated isotopomers

Diverse Cell Type-Specific Mechanisms Localize G Protein-Coupled Receptors to Caenorhabditis elegans Sensory Cilia

Signaling by olfactory receptor neurons near threshold

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