Direct demonstration of a physiological role for carbon monoxide in olfactory receptor neurons

Ingi, Tatsuya; Ronnett, Gabriele V.

doi:10.1523/jneurosci.15-12-08214.1995

Cited by 102 publications

(83 citation statements)

References 35 publications

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“…On the other hand, several enzymes other than NOS require electrons from NADPH, and some of them are known to be expressed in the rat olfactory mucosa [8,16,22]. For example, isoforms of cytochrome P450 enzymes; NMa, NMb, and CYP2F are expressed in the apical cytoplasm of supporting cells and Bowman's glands in the rat olfactory mucosa [8,16].…”

Section: Discussionmentioning

confidence: 99%

Localization of eNOS in the Olfactory Epithelium of the Rat

Endo

Yamamoto

Yamaguchi-Yamada

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. Nitric oxide (NO) is a free radical and produced from L-arginine by nitric oxide synthase (NOS). Since NO is recently suggested to be involved in olfactory perception, the expression of eNOS, an isoform of NOS, was examined in the rat olfactory epithelium. The activity of NADPH-diaphorase was also examined as a marker of NOS. In the dorsomedial region of the nasal cavity, intensely positive reactions for NADPH-diaphorase were observed in the entire cytoplasm of sensory cells (olfactory cells). By immunohistochemistry, intensely positive reactions for eNOS were also found in the dorsomedial region of the nasal cavity. These reactions were observed on the free border of the olfactory epithelium. By immunoelectron microscopy, positive reactions for eNOS were found in the cilia of olfactory cells. In addition, in situ hybridization analysis of the olfactory epithelium revealed the expression of eNOS mRNA in the olfactory cells. These results indicate the presence of eNOS in the olfactory cells of the rat, and differential expression of eNOS in the olfactory epithelium depending on the regions of the nasal cavity. In addition, NO produced by eNOS may be involved in olfactory perception in the cilia of olfactory cells.KEY WORDS: eNOS, NADPH-diaphorase, nitric oxide, olfactory epithelium, rat.J. Vet. Med. Sci. 73(4): 423-430, 2011 Nitric oxide (NO) is a free radical with many functions in the cardiovascular, nervous, and immune systems [2]. Biologically, NO is produced from L-arginine by nitric oxide synthase (NOS). NOS is divided into 3 types of major isoforms, i.e., neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). The nNOS and eNOS are constitutive forms of NOS and mainly expressed in the neuronal and endothelial cells, respectively. The iNOS is an inducible form of NOS and mainly expressed in macrophages [15].Primary function of NO is the activation of soluble guanylyl cyclase (sGC) to increase cGMP levels [1]. In the cilia of the rat sensory cells (olfactory cells), it is reported that odorant-stimulus induces the increase of cGMP levels and that specific NOS inhibitor L-N G -nitro arginine or NO scavenger hemoglobin inhibits this increase [4]. These findings indicate that odorant-stimulus induces NO production in the rat olfactory cells. Schmachtenberg et al. (2000Schmachtenberg et al. ( , 2003 reported that NO-stimulus induces outward potassium currents in 30 out of 72 olfactory cells and inward potassium currents in 3 out of 54 cells by physiological study [36,37]. In the cilia of rat olfactory cells, moreover, NO-stimulus is reported to activate or inhibit olfactory cyclic nucleotidegated (CNG) channels [5,6,28,36,37]. These reports suggest that NO is produced by the olfactory cells in response to odorant-stimulus, and has inhibitory and/or weakly excitatory effects to the olfactory cells by gating of CNG channel. However, it is still unclear which type of NOS isoforms generates NO in the olfactory cells of the rat. Because it has been reported that iNOS and eNOS are expressed...

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Section: Discussionmentioning

confidence: 99%

Localization of eNOS in the Olfactory Epithelium of the Rat

Endo

Yamamoto

Yamaguchi-Yamada

et al. 2011

The Journal of Veterinary Medical Science

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“…We do not know whether their actions are additive or synergistic. In olfactory tissue, there is evidence that CO may act as a partial agonist of sGC, related to its weaker activity than NO in stimulating the enzyme (59)(60)(61). Whether this occurs in the gut remains to be established.…”

Section: Physiologic Rolesmentioning

confidence: 99%

Neural roles for heme oxygenase: Contrasts to nitric oxide synthase

Barañano

Snyder

2001

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

277

204

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The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's Nmethyl-D-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.

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“…Removal of extracellular Ca 2ϩ results in a less transient cAMP-induced whole-cell current and eliminates the phasic-tonic behavior of odor currents during maintained stimulation (Kurahashi, 1990;Kurahashi and Shibuya, 1990;Zufall et al, 1991b;Kurahashi and Menini, 1997). Ca 2ϩ -dependent feedback regulation also can be initiated by the CO/ cGMP signaling system (Verma et al, 1993;Ingi and Ronnett, 1995;Leinders-Zufall et al, 1995a), which leads, via persistent activation of CNG channels by cGMP, to the induction of a long-lasting form of odor adaptation Zufall and Leinders-Zufall, 1997). Collectively, these results reveal complex effects of [Ca 2ϩ ] i in ORNs.…”

Section: Abstract: Olfactory Receptor Neurons; Cilia; Confocal Micromentioning

confidence: 99%

Calcium Entry through Cyclic Nucleotide-Gated Channels in Individual Cilia of Olfactory Receptor Cells: Spatiotemporal Dynamics

et al. 1997

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Transient elevations of intracellular Ca 2ϩ play an important role in regulating the sensitivity of olfactory transduction, but such elevations have not been demonstrated in the olfactory cilia, which are the site of primary odor transduction. To begin to understand Ca 2ϩ signaling in olfactory cilia, we used highresolution imaging techniques to study the Ca 2ϩ transients that occur in salamander olfactory receptor neurons (ORNs) as a result of cyclic nucleotide-gated (CNG) channel activation. To visualize ciliary Ca 2ϩ signals, we loaded ORNs with the Ca 2ϩ indicator dye Fluo-3 AM and measured fluorescence with a laser scanning confocal microscope. Application of the phosphodiesterase inhibitor IBMX increased fluorescence in the cilia and other neuronal compartments; the ciliary signal occurred first and was more transient. This signal could be abolished by lowering external Ca 2ϩ or by applying LY83583, a potent blocker of CNG channels, indicating that Ca 2ϩ entry through CNG channels was the primary source of fluorescence increases. Direct activation of CNG channels with low levels of 8-Br-cGMP (1 M) led to tonic Ca 2ϩ signals that were restricted locally to the cilia and the dendritic knob. Elevated external K ϩ , which depolarizes cell membranes, increased fluorescence signals in the cell body and dendrite but failed to increase ciliary Ca 2ϩ fluorescence. The results demonstrate the existence and spatiotemporal properties of Ca 2ϩ transients in individual olfactory cilia and implicate CNG channels as a major pathway for Ca 2ϩ entry into ORN cilia during odor transduction.

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Direct demonstration of a physiological role for carbon monoxide in olfactory receptor neurons

Cited by 102 publications

References 35 publications

Localization of eNOS in the Olfactory Epithelium of the Rat

Localization of eNOS in the Olfactory Epithelium of the Rat

Neural roles for heme oxygenase: Contrasts to nitric oxide synthase

Calcium Entry through Cyclic Nucleotide-Gated Channels in Individual Cilia of Olfactory Receptor Cells: Spatiotemporal Dynamics

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