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Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium
Ruth Dooley, Anastasia Mashukova, Bastian Toetter, Hanns Hatt, Eva M Neuhaus
BMC Neuroscience , 2011, DOI: 10.1186/1471-2202-12-86
Abstract: Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells.Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.Odorant receptors (OR) are G protein-coupled receptors which are expressed in olfactory sensory neurons (OSN) of the mammalian olfactory epithelium (OE) [1-3]. Each OSN expresses only one particular type of OR [4] and a given OR gene is expressed in a small subset of OSNs [5,6]. All neurons expressing a particular receptor converge to a single target in the olfactory bulb [5-7]. A total of 347 putative functional OR genes are found in human [8] and approximately 1000 in mouse [9]. Odorant-specific signal transduction is mediated via the olfactory G protein Gαolf [10], adenylyl cyclase type III activation [11], the concomitant cAMP-mediated activation of a cyclic nucleotide-gated (CNG) channel [12-15] and the opening of a Ca2+ gated Cl- channel [16,17]. The OE is made up of 3 main cell types: OSNs, basal cells which maintain the regenerative capacity of the OE [18,19] and glial-like sustentacular supporting cells. It is likely that sustentacular cells, as is the case for other glial subtypes of the nervous system, function not only in the maintenance and s
Activity-Dependent Modulation of Odorant Receptor Gene Expression in the Mouse Olfactory Epithelium  [PDF]
Shaohua Zhao, Huikai Tian, Limei Ma, Ying Yuan, C. Ron Yu, Minghong Ma
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069862
Abstract: Activity plays critical roles in development and maintenance of the olfactory system, which undergoes considerable neurogenesis throughout life. In the mouse olfactory epithelium, each olfactory sensory neuron (OSN) stably expresses a single odorant receptor (OR) type out of a repertoire of ~1200 and the OSNs with the same OR identity are distributed within one of the few broadly-defined zones. However, it remains elusive whether and how activity modulates such OR expression patterns. Here we addressed this question by investigating OR gene expression via in situ hybridization when sensory experience or neuronal excitability is manipulated. We first examined the expression patterns of fifteen OR genes in mice which underwent neonatal, unilateral naris closure. After four-week occlusion, the cell density in the closed (sensory-deprived) side was significantly lower (for four ORs), similar (for three ORs), or significantly higher (for eight ORs) as compared to that in the open (over-stimulated) side, suggesting that sensory inputs have differential effects on OSNs expressing different OR genes. We next examined the expression patterns of seven OR genes in transgenic mice in which mature OSNs had reduced neuronal excitability. Neuronal silencing led to a significant reduction in the cell density for most OR genes tested and thinner olfactory epithelium with an increased density of apoptotic cells. These results suggest that sensory experience plays important roles in shaping OR gene expression patterns and the neuronal activity is critical for survival of OSNs.
Odorant Metabolism Catalyzed by Olfactory Mucosal Enzymes Influences Peripheral Olfactory Responses in Rats  [PDF]
Nicolas Thiebaud, Stéphanie Veloso Da Silva, Ingrid Jakob, Gilles Sicard, Jo?lle Chevalier, Franck Ménétrier, Olivier Berdeaux, Yves Artur, Jean-Marie Heydel, Anne-Marie Le Bon
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059547
Abstract: A large set of xenobiotic-metabolizing enzymes (XMEs), such as the cytochrome P450 monooxygenases (CYPs), esterases and transferases, are highly expressed in mammalian olfactory mucosa (OM). These enzymes are known to catalyze the biotransformation of exogenous compounds to facilitate elimination. However, the functions of these enzymes in the olfactory epithelium are not clearly understood. In addition to protecting against inhaled toxic compounds, these enzymes could also metabolize odorant molecules, and thus modify their stimulating properties or inactivate them. In the present study, we investigated the in vitro biotransformation of odorant molecules in the rat OM and assessed the impact of this metabolism on peripheral olfactory responses. Rat OM was found to efficiently metabolize quinoline, coumarin and isoamyl acetate. Quinoline and coumarin are metabolized by CYPs whereas isoamyl acetate is hydrolyzed by carboxylesterases. Electro-olfactogram (EOG) recordings revealed that the hydroxylated metabolites derived from these odorants elicited lower olfactory response amplitudes than the parent molecules. We also observed that glucurono-conjugated derivatives induced no olfactory signal. Furthermore, we demonstrated that the local application of a CYP inhibitor on rat olfactory epithelium increased EOG responses elicited by quinoline and coumarin. Similarly, the application of a carboxylesterase inhibitor increased the EOG response elicited by isoamyl acetate. This increase in EOG amplitude provoked by XME inhibitors is likely due to enhanced olfactory sensory neuron activation in response to odorant accumulation. Taken together, these findings strongly suggest that biotransformation of odorant molecules by enzymes localized to the olfactory mucosa may change the odorant’s stimulating properties and may facilitate the clearance of odorants to avoid receptor saturation.
Spatiotemporal Alterations in Primary Odorant Representations in Olfactory Marker Protein Knockout Mice  [PDF]
Marley D. Kass, Andrew H. Moberly, John P. McGann
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061431
Abstract: Olfactory marker protein (OMP) is highly and selectively expressed in primary olfactory sensory neurons (OSNs) across species, but its physiological function remains unclear. Previous studies in the olfactory epithelium suggest that it accelerates the neural response to odorants and may modulate the odorant-selectivity of OSNs. Here we used a line of gene-targeted mice that express the fluorescent exocytosis indicator synaptopHluorin in place of OMP to compare spatiotemporal patterns of odorant-evoked neurotransmitter release from OSNs in adult mice that were heterozygous for OMP or OMP-null. We found that these patterns, which constitute the primary neural representation of each odorant, developed more slowly during the odorant presentation in OMP knockout mice but eventually reached the same magnitude as in heterozygous mice. In the olfactory bulb, each glomerulus receives synaptic input from a subpopulation of OSNs that all express the same odor receptor and thus typically respond to a specific subset of odorants. We observed that in OMP knockout mice, OSNs innervating a given glomerulus typically responded to a broader range of odorants than in OMP heterozygous mice and thus each odorant evoked synaptic input to a larger number of glomeruli. In an olfactory habituation task, OMP knockout mice behaved differently than wild-type mice, exhibiting a delay in their onset to investigate an odor stimulus during its first presentation and less habituation to that stimulus over repeated presentations. These results suggest that the actions of OMP in olfactory transduction carry through to the primary sensory representations of olfactory stimuli in adult mice in vivo.
Odorant-Dependent Generation of Nitric Oxide in Mammalian Olfactory Sensory Neurons  [PDF]
Daniela Brunert, Stefan Kurtenbach, Sonnur Isik, Heike Benecke, Günter Gisselmann, Wolfgang Schuhmann, Hanns Hatt, Christian H. Wetzel
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005499
Abstract: The gaseous signalling molecule nitric oxide (NO) is involved in various physiological processes including regulation of blood pressure, immunocytotoxicity and neurotransmission. In the mammalian olfactory bulb (OB), NO plays a role in the formation of olfactory memory evoked by pheromones as well as conventional odorants. While NO generated by the neuronal isoform of NO synthase (nNOS) regulates neurogenesis in the olfactory epithelium, NO has not been implicated in olfactory signal transduction. We now show the expression and function of the endothelial isoform of NO synthase (eNOS) in mature olfactory sensory neurons (OSNs) of adult mice. Using NO-sensitive micro electrodes, we show that stimulation liberates NO from isolated wild-type OSNs, but not from OSNs of eNOS deficient mice. Integrated electrophysiological recordings (electro-olfactograms or EOGs) from the olfactory epithelium of these mice show that NO plays a significant role in modulating adaptation. Evidence for the presence of eNOS in mature mammalian OSNs and its involvement in odorant adaptation implicates NO as an important new element involved in olfactory signal transduction. As a diffusible messenger, NO could also have additional functions related to cross adaptation, regeneration, and maintenance of MOE homeostasis.
Odorant receptor expressed sequence tags demonstrate olfactory expression of over 400 genes, extensive alternate splicing and unequal expression levels
Janet M Young, Benjamin M Shykind, Robert P Lane, Lori Tonnes-Priddy, Joseph A Ross, Megan Walker, Eleanor M Williams, Barbara J Trask
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-11-r71
Abstract: We identified more than 1,200 odorant receptor cDNAs representing more than 400 genes. Using real-time PCR to confirm expression level differences suggested by our screen, we find that transcript levels in the olfactory epithelium can differ between olfactory receptors by up to 300-fold. Differences for one gene pair are apparently due to both unequal numbers of expressing cells and unequal transcript levels per expressing cell. At least two-thirds of olfactory receptors exhibit multiple transcriptional variants, with alternative isoforms of both 5' and 3' untranslated regions. Some transcripts (5%) utilize splice sites within the coding region, contrary to the stereotyped olfactory receptor gene structure. Most atypical transcripts encode nonfunctional olfactory receptors, but can occasionally increase receptor diversity.Our cDNA collection confirms olfactory function of over one-third of the intact mouse olfactory receptors. Most of these genes were previously annotated as olfactory receptors based solely on sequence similarity. Our finding that different olfactory receptors have different expression levels is intriguing given the one-neuron, one-gene expression regime of olfactory receptors. We provide 5' untranslated region sequences and candidate promoter regions for more than 300 olfactory receptors, valuable resources for computational regulatory motif searches and for designing olfactory receptor microarrays and other experimental probes.The interaction of olfactory (or odorant) receptors with their odorant ligands is the first step in a signal transduction pathway that results in the perception of smell. The olfactory receptor gene family is one of the largest in the mammalian genome, comprising about 1,500 members in the mouse genome [1,2]. Olfactory receptors were originally identified in an elegant experiment based on the hypothesis that they would be seven-transmembrane-domain proteins encoded by a large, diverse gene family whose expression is restrict
Olfactory discrimination largely persists in mice with defects in odorant receptor expression and axon guidance
Thomas K Knott, Pasil A Madany, Ashley A Faden, Mei Xu, J?rg Strotmann, Timothy R Henion, Gerald A Schwarting
Neural Development , 2012, DOI: 10.1186/1749-8104-7-17
Abstract: Microarray analysis reveals that nearly one quarter of all odorant receptor genes are down regulated in β3GnT2?/? mice compared to controls. Analysis of OR expression by quantitative PCR and in situ hybridization demonstrates that the number of neurons expressing some odorant receptors, such as mOR256-17, is increased by nearly 60% whereas for others such as mOR28 the number of neurons is decreased by more than 75% in β3GnT2?/? olfactory epithelia. Analysis of axon trajectories confirms that many axons track to inappropriate targets in β3GnT2?/? mice, and some glomeruli are populated by axons expressing more than one odorant receptor. Results show that mutant mice perform nearly as well as control mice in an odor discrimination task. In addition, in situ hybridization studies indicate that the expression of several activity dependent genes is unaffected in β3GnT2?/? olfactory neurons.Results presented here show that many odorant receptors are under-expressed in β3GnT2?/? mice and further demonstrate that additional axon subsets grow into inappropriate targets or minimally innervate glomeruli in the olfactory bulb. Odor evoked gene expression is unchanged and β3GnT2?/? mice exhibit a relatively small deficit in their ability to discriminate divergent odors. Results suggest that despite the fact that β3GnT2?/? mice have decreased AC3 activity, decreased expression of many ORs, and display many axon growth and guidance errors, odor-evoked activity in cilia of mutant olfactory neurons remains largely intact.Understanding the organization of connections in the mammalian olfactory system is a challenge because the rules used to generate a map of axon trajectories from the olfactory epithelium to the olfactory bulb (OB) appear to differ considerably from other sensory modalities, such as the visual and somatosensory systems [1-3]. It is now clear that regulation of adenylyl cyclase activity and generation of cAMP is one of the major contributors of guidance information in
Early survival factor deprivation in the olfactory epithelium enhances activity-driven survival  [PDF]
Adrien Fran?ois,Edith Pajot-Augy,Nicolas Meunier
Frontiers in Cellular Neuroscience , 2013, DOI: 10.3389/fncel.2013.00271
Abstract: The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs). However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226). We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population toward detection of environmental odorants.
Expressing exogenous functional odorant receptors in cultured olfactory sensory neurons
Huaiyang Chen, Sepehr Dadsetan, Alla F Fomina, Qizhi Gong
Neural Development , 2008, DOI: 10.1186/1749-8104-3-22
Abstract: We demonstrate that cultured olfactory sensory neurons express endogenous odorant receptors. Lentiviral vector-mediated gene transfer enables successful ectopic expression of odorant receptors. We show that the ectopically expressed mouse I7 is functional in the cultured olfactory sensory neurons. When two different odorant receptors are ectopically expressed simultaneously, both receptor proteins co-localized in the same olfactory sensory neurons up to 10 days in vitro.This culture technique provided an efficient method to culture olfactory sensory neurons whose morphology, molecular characteristics and maturation progression resembled those observed in vivo. Using this system, regulation of odorant receptor expression and its ligand specificity can be studied in its intrinsic cellular environment.It is established that most of the olfactory sensory neurons (OSNs) express only one type of odorant receptor (OR) among a thousand gene choices [1,2]. Each OSN functions as a specialized sensor for the detection of diverse odorants in the environment. OSNs expressing the same OR converge their axons to the same glomerular pair in the olfactory bulb [3,4]. Thus, the one receptor-one neuron rule is essential for establishing the discrete sensory map of olfactory neuronal connections.The ability to discriminate odorants in the environment depends on OR-ligand interactions and signaling capacity within the OSNs. Several experimental approaches for investigating OR functions have been reported [5-8]. Though heterologous systems allow rapid screening of ligand binding specificity of the ORs, validation of these results in the OSNs has been challenging without an efficient OSN culture system [9]. One of the other challenges in olfaction is to understand the regulatory mechanism for OR selection in the OSNs. Transcriptional regulatory elements that control OR expression have been identified [10,11]. In addition, a negative feedback model for achieving single OR expression in eac
Role of nitric oxide during neurogenesis in the olfactory epithelium
Biological Research , 2006, DOI: 10.4067/S0716-97602006000500002
Abstract: in mammals, neurogenesis continues during adulthood in restricted places of the nervous system, namely the subventricular zone, the dentate gyms and the olfactory epithelium. a dual role of the second messenger nitric oxide has been reported in such places, either promoting or inhibiting proliferation of neuronal precursors depending on the cellular signal implicated. in this review the regulation of adult olfactory epithelium neurogenesis by nitric oxide is discussed
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