Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Ikegami, Kentaro; March, Claire A. de; Nagai, Maíra H.; Ghosh, Soumadwip; Do, Matthew; Sharma, Ruchira; Bruguera, Elise S.; Lu, Yueyang; Fukutani, Yosuke; Vaidehi, Nagarajan; Yohda, Masafumi; Matsunami, Hiroaki

doi:10.1073/pnas.1915520117

Cited by 41 publications

(48 citation statements)

References 70 publications

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“…For a long time, it has been difficult to correlate a given OR to its specific cognate ligands. The biggest obstacle in this process was the impossibility to express functional ORs in heterologous systems, because of the OR retention in the endoplasmic reticulum and subsequent OR degradation in the proteasome [ 59 , 60 ]. Firestein group overcame this limitation using the olfactory epithelium as an expression system and exploited adenovirus vectors expressing I7-OR to drive the expression of I7-OR in a large population of OSNs.…”

Section: Introductionmentioning

confidence: 99%

The role of the odorant receptors in the formation of the sensory map

Francia

Lodovichi

2021

BMC Biol

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In the olfactory system, odorant receptors (ORs) expressed at the cell membrane of olfactory sensory neurons detect odorants and direct sensory axons toward precise target locations in the brain, reflected in the presence of olfactory sensory maps. This dual role of ORs is corroborated by their subcellular expression both in cilia, where they bind odorants, and at axon terminals, a location suitable for axon guidance cues. Here, we provide an overview and discuss previous work on the role of ORs in establishing the topographic organization of the olfactory system and recent findings on the mechanisms of activation and function of axonal ORs.

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Section: Introductionmentioning

confidence: 99%

The role of the odorant receptors in the formation of the sensory map

Francia

Lodovichi

2021

BMC Biol

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“…Vindija F159L4.58 is in the extracellular part of TM4 (Fig. 3), near 4.53, which is involved in mouse OR trafficking (24). We observed slightly lower trafficking of the Vindija protein.…”

Section: Resultsmentioning

confidence: 60%

“…The cell surface expression of the Rho-tagged ORs was evaluated as described in Ikegami, de March et al (24). HEK293 cells were plated in 35 mm plates at 25% confluency and grown overnight at 37°C and 5% CO2.…”

Section: Flowcytometrymentioning

confidence: 99%

Genetic and functional odorant receptor variation in the Homo lineage

March

Matsunami

Cobb

et al. 2021

Preprint

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The largest and rapidly evolving gene family of odorant receptors detect odors to variable degrees due to amino acid sequence and protein structure. Hybridization between humans, Neandertals, and Denisovans implies shared behavior, although some speculate that Neandertals were poor smellers. We identified genetic and functional variation in humans and extinct lineages in 30 receptors with known function. We show that structural changes in receptor proteins altered odor sensitivity not specificity, indicating a common repertoire across lineages. In humans, variation in receptors may change odor perception or induce odor-specific anosmia. Variation in sensitivity may reflect local adaptations (e.g., Denisovan sensitivity to honey, Neandertals sensitivity to grass and sulphur). Extinct human lineages had highly conserved receptor genes and proteins. We observe a similar pattern in the Neandertal OR5P3 variant, which produced no response to ~350 odors. Our data suggest that receptor structure was highly conserved in our closest relatives, but not in living humans. The diversity of geographic adaptations in humans may have produced greater functional variation, increasing our olfactory repertoire and expanding our adaptive capacity. Our results provide insight into odorant receptor function and shed light on the olfactory ecology of ancient humans and their extinct relatives. By studying the function of ancient odorant receptor genes, we have been able to get a glimpse of the sensory world of our extinct ancestors and relatives, with some of the variants giving specific insights into potential adaptations shown by these long-dead populations. The functional variability we have identified in the molecular structure of the odorant receptor proteins will aid in the more general problem of understanding the function of odorant receptor proteins and the neurons they are carried by, opening the road to linking receptor function to perception.

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“…Mammalian ORs are affected by similar problems regarding an incorrect intracellular trafficking in heterologous expression systems. Although specific classes of proteins have been shown to support the trafficking of mammalian ORs in native olfactory neurons and in heterologous systems (Saito et al 2004; Mainland and Matsunami 2012), conserved OR residues linked to in silico structural stability were shown to impact their functional expression (Ikegami et al 2019); we cannot exclude that insect ORs are subject to similar structural constraints.…”

Section: Discussionmentioning

confidence: 99%

Optimization of Insect Odorant Receptor Trafficking and Functional Expression Via Transient Transfection in HEK293 Cells

et al. 2019

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Insect odorant receptors (ORs) show a limited functional expression in various heterologous expression systems including insect and mammalian cells. This may be in part due to the absence of key components driving the release of these proteins from the endoplasmic reticulum and directing them to the plasma membrane. In order to mitigate this problem, we took advantage of small export signals within the human HCN1 and Rhodopsin that have been shown to promote protein release from the endoplasmic reticulum and the trafficking of post-Golgi vesicles, respectively. Moreover, we designed a new vector based on a bidirectional expression cassette to drive the functional expression of the insect odorant receptor coreceptor (Orco) and an odor-binding OR, simultaneously. We show that this new method can be used to reliably express insect ORs in HEK293 cells via transient transfection and that is highly suitable for downstream applications using automated and high-throughput imaging platforms.

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Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

Cited by 41 publications

References 70 publications

The role of the odorant receptors in the formation of the sensory map

The role of the odorant receptors in the formation of the sensory map

Genetic and functional odorant receptor variation in the Homo lineage

Optimization of Insect Odorant Receptor Trafficking and Functional Expression Via Transient Transfection in HEK293 Cells

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