Structural determinants of odorant recognition by the human olfactory receptors OR1A1 and OR1A2

Schmiedeberg, Kristin; Shirokova, Elena A.; Weber, Hans‐Peter; Schilling, Boris; Meyerhof, Wolfgang; Krautwurst, Dietmar

doi:10.1016/j.jsb.2007.04.013

Cited by 145 publications

(165 citation statements)

References 33 publications

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“…In agreement with our hypothesis, apical stimulation of primary culture cells with a panel of volatile chemicals that have been shown to activate some of the receptors expressed in hTECs ( Figure 1A and Table E2) resulted in a significant increase of CGRP released into the basal cell medium ( Figure 3C). In addition, staining of hTEC preparations that were treated with the ligands, nonanal (36) or citronellal (37), showed overall lower 5-HT signal relative to that in DMSO-treated cells. Together, these results are consistent with stimulation-dependent release of CGRP and 5-HT ( Figures 3D and 3E).…”

Section: Resultsmentioning

confidence: 99%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

126

108

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The mammalian airways are sensitive to inhaled stimuli, and airway diseases are characterized by hypersensitivity to volatile stimuli, such as perfumes, industrial solvents, and others. However, the identity and function of the cells in the airway that can sense volatile chemicals remain uncertain, particularly in humans. Here, we show that solitary pulmonary neuroendocrine cells (PNECs), which are morphologically distinct and physiologically undefined, might serve as chemosensory cells in human airways. This conclusion is based on our finding that some human PNECs expressed members of the olfactory receptor (OR) family in vivo and in primary cell culture, and are anatomically positioned in the airway epithelium to respond to inhaled volatile chemicals. Furthermore, apical exposure of primaryculture human airway epithelial cells to volatile chemicals decreased levels of serotonin in PNECs, and the led to the release of the neuropeptide calcitonin gene-related peptide (CGRP) to the basal medium. These data suggest that volatile stimulation of PNECs can lead to the secretion of factors that are capable of stimulating the corresponding receptors in the lung epithelium. We also found that the distribution of serotonin and neuropeptide receptors may change in chronic obstructive pulmonary disease, suggesting that increased PNEC-dependent chemoresponsiveness might contribute to the altered sensitivity to volatile stimuli in this disease. Together, these data indicate that human airway epithelia harbor specialized cells that respond to volatile chemical stimuli, and may help to explain clinical observations of odorant-induced airway reactions.

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Section: Resultsmentioning

confidence: 99%

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Karp

Brody

et al. 2014

Am J Respir Cell Mol Biol

126

108

View full text Add to dashboard Cite

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“…After the elucidation of a second GPCR structure in 2007, that of the human β2 adrenergic receptor, questions related to the applicability of rhodopsin as a model for other GPCR structures were eventually settled, and most models were then based on the homology modeling approach using the available high-resolution GPCR structures as templates. After 2005, the results of the OR modeling and ligand docking in silico simulations were systematically validated by site-directed mutagenesis experiments and functional assays in an effort to better understand the characteristics of ligand recognition by ORs [screening of large odorant libraries and determination of functional fingerprints (Baud et al 2010), characterization of 'odotypes' (Schmiedeberg et al 2007;Stary et al 2007), correlation between the ligand concentration required for 50 % activation of the receptor (EC50), and the computed binding energy (Kurland et al 2010), among others]. Due to the difficulty of aligning some of the OR TMHs, most proposed models 2.8 Å bovine rhodopsin 3D structure Schmiedeberg et al 2007 This work is related to that in (Stary et al 2007).…”

Section: Application To Structure Modeling and Virtual Screening Of Orsmentioning

confidence: 99%

“…After 2005, the results of the OR modeling and ligand docking in silico simulations were systematically validated by site-directed mutagenesis experiments and functional assays in an effort to better understand the characteristics of ligand recognition by ORs [screening of large odorant libraries and determination of functional fingerprints (Baud et al 2010), characterization of 'odotypes' (Schmiedeberg et al 2007;Stary et al 2007), correlation between the ligand concentration required for 50 % activation of the receptor (EC50), and the computed binding energy (Kurland et al 2010), among others]. Due to the difficulty of aligning some of the OR TMHs, most proposed models 2.8 Å bovine rhodopsin 3D structure Schmiedeberg et al 2007 This work is related to that in (Stary et al 2007). Using site-directed mutagenesis and functional expression the authors show that the orientation of odorants within a homo logy modelingderived binding pocket of olfactory receptor orthologs is defined by evolutionary conserved amino acid positions.…”

Section: Application To Structure Modeling and Virtual Screening Of Orsmentioning

confidence: 99%

Modeling of mammalian olfactory receptors and docking of odorants

et al. 2012

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Olfactory receptors (ORs) belong to the superfamily of G protein-coupled receptors (GPCRs), the second largest class of genes after those related to immunity, and account for about 3 % of mammalian genomes. ORs are present in all multicellular organisms and represent more than half the GPCRs in mammalian species (e.g., the mouse OR repertoire contains >1,000 functional genes). ORs are mainly expressed in the olfactory epithelium where they detect odorant molecules, but they are also expressed in a number of other cells, such as sperm cells, although their functions in these cells remain mostly unknown. It has recently been reported that ORs are present in tumoral tissues where they are expressed at different levels than in healthy tissues. A specific OR is overexpressed in prostate cancer cells, and activation of this OR has been shown to inhibit the proliferation of these cells. Odorant stimulation of some of these receptors results in inhibition of cell proliferation. Even though their biological role has not yet been elucidated, these receptors might constitute new targets for diagnosis and therapeutics. It is important to understand the activation mechanism of these receptors at the molecular level, in particular to be able to predict which ligands are likely to activate a particular receptor ('deorphanization') or to design antagonists for a given receptor. In this review, we describe the in silico methodologies used to model the three-dimensional (3D) structure of ORs (in the more general framework of GPCR modeling) and to dock ligands into these 3D structures.

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“…In contrast to the ER, the molecular determinants governing the interactions between odorants and their corresponding ORs are less well understood due to lack of experimentally determined high resolution structures and specific binding affinity data for this large family of GPCRs. The binding sites of a few ORs have been modeled on the basis of the known crystallographic structure of rhodopsin (26,67,68) or by assembling and optimizing the packing of the seven-helix TM bundle of ORs in lipid bilayer (69). Alternatively, an approach to classify OR binding sites based on sequence comparison has been proposed (70).…”

mentioning

confidence: 99%

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Pick

Etter

Baud

et al. 2009

Journal of Biological Chemistry

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We have screened an odorant compound library and discovered molecules acting as chemical signals that specifically activate both G-protein-coupled olfactory receptors (ORs) on the cell surface of olfactory sensory neurons and the human nuclear estrogen receptor ␣ (ER) involved in transcriptional regulation of cellular differentiation and proliferation in a wide variety of tissues. Hence, these apparent dual active odorants induce distinct signal transduction pathways at different subcellular localizations, which affect both neuronal signaling, resulting in odor perception, and the ER-dependent transcriptional control of specific genes. We demonstrate these effects using fluorescence-based in vitro and cellular assays. Among these odorants, we have identified synthetic sandalwood compounds, an important class of molecules used in the fragrance industry. For one estrogenic odorant we have also identified the cognate OR. This prompted us to compare basic molecular recognition principles of odorants on the two structurally and apparent functionally non-related receptors using computational modeling in combination with functional assays. Faced with the increasing evidence that ORs may perform chemosensory functions in a number of tissues outside of the nasal olfactory epithelium, the unraveling of these molecular ligand-receptor interaction principles is of critical importance. In addition the evidence that certain olfactory sensory neurons naturally co-express ORs and ERs may provide a direct functional link between the olfactory and hormonal systems in humans. Our results are therefore useful for defining the structural and functional characteristics of ER-specific odorants and the role of odorant molecules in cellular processes other than olfaction.Our nose detects a large variety of odorant signals relying on about 350 different predicted G-protein-coupled olfactory receptors (ORs) 3 with a conserved seven-transmembrane helical structure (1-3). By binding odorant molecules ORs modulate the conversion of chemical into electrical neuronal signals that are finally decoded in higher brain regions to trigger emotional and behavioral responses (4 -6). Odorants are generally small, hydrophobic organic molecules with highly variable chemical structures and properties (7). They easily pass cell membranes, and, due to their enormous chemical diversity, some of them might, apart from their "conventional" role in olfaction, trigger also yet unknown cellular processes. The role of specific ORs in sperm chemotaxis has been documented (8,9), and the widespread ectopic expression of OR genes in a large number of non-olfactory human tissues implicates additional, unproven functions of ORs in embryonic development and cell-cell recognition (10), and proliferation rates in prostate cancer cells (11). Recent findings indicate that ORs might also have chemosensory functions in kidney (12). Although most present efforts concentrate on matching odorants with their cognate ORs to define their molecular receptive ranges and receptor fu...

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Structural determinants of odorant recognition by the human olfactory receptors OR1A1 and OR1A2

Cited by 145 publications

References 33 publications

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Chemosensory Functions for Pulmonary Neuroendocrine Cells

Modeling of mammalian olfactory receptors and docking of odorants

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

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