Hypoxia sensing requires H
            <sub>2</sub>
            S-dependent persulfidation of olfactory receptor 78

Peng, Ying; Nanduri, Jayasri; Wang, Ning; Kumar, Ganesh K.; Bindokas, Vytas P.; Paul, Bindu D.; Chen, Xuanmao; Fox, Aaron P.; Vignane, Thibaut; Filipović, Miloš R.; Prabhakar, Nanduri R.

doi:10.1126/sciadv.adf3026

Cited by 10 publications

(8 citation statements)

References 41 publications

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“… 13 A report showed that redox modification of Olfr78 participates in carotid body activation by hypoxia to regulate breathing. 46 The results consistent with the above reports were observed in our study, the expression of Olfr78 was significantly decreased after hypoxic injury. In addition, some studies have shown that the release of inflammatory factors caused by NLRP3 inflammasome activation is a significant pathological feature of cardiovascular disease and brain injury.…”

Section: Discussionsupporting

confidence: 93%

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Kang,

Zhu,

Xue

et al. 2024

J Cellular Molecular Medi

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Ischemic stroke is one of the main causes of disability and death. However, recanalization of occluded cerebral arteries is effective only within a very narrow time window. Therefore, it is particularly important to find neuroprotective biological targets for cerebral artery recanalization. Here, gene expression profiles of datasets GSE160500 and GSE97537 were downloaded from the GEO database, which were related to ischemic stroke in rats. Olfactory receptor 78 (Olfr78) was screened, and which highly associated with Calcium signalling pathway and MAPK pathway. Interacting protein of Olfr78, Prkaca, was predicted by STRING, and their interaction was validated by Co‐IP analysis. Then, a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a neuronal cell model stimulated by oxygen–glucose deprivation/reoxygenation (OGD/R) were constructed, and the results showed that expression of Olfr78 and Prkaca was downregulated in MCAO rats and OGD/R‐stimulated neurons. Overexpression of Olfr78 or Prkaca inhibited the secretion of inflammatory factors, Ca2+ overload, and OGD/R‐induced neuronal apoptosis. Moreover, Overexpression of Prkaca increased protein levels of cAMP, PKA and phosphorylated p38 in OGD/R‐stimulated neurons, while SB203580, a p38 inhibitor, treatment inhibited activation of the cAMP/PKA‐MAPK pathway and counteracted the effect of Olfr78 overexpression on improvement of neuronal functions. Meanwhile, overexpression of Olfr78 or Prkaca markedly inhibited neuronal apoptosis and improved brain injury in MCAO/R rats. In conclusion, overexpression of Olfr78 inhibited Ca2+ overload and reduced neuronal apoptosis in MCAO/R rats by promoting Prkaca‐mediated activation of the cAMP/PKA‐MAPK pathway, thereby improving brain injury in cerebral ischaemia–reperfusion.

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Section: Discussionsupporting

confidence: 93%

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Kang,

Zhu,

Xue

et al. 2024

J Cellular Molecular Medi

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“… 45 Mice with glomus cells deficient in adenylate cyclase 3, a key component of the olfactory signal transduction pathway, exhibit impaired cellular and breathing responses to hypoxia. 46 The physiological ligand(s) of Olfr78 is (are) unknown and the possibility that this G-protein-coupled receptor is constitutively activated 47 cannot be discounted.…”

Section: Discussionmentioning

confidence: 99%

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

Colinas,

Mombaerts,

López-Barneo

et al. 2024

Function

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The Olfr78 gene encodes a G-protein coupled receptor that is expressed in olfactory sensory neurons, where it functions as a conventional odorant receptor, and also in several ectopic sites, where its function is not well understood. Olfr78 is one of the most highly expressed mRNA species in glomus cells of the carotid body (CB). These cells are the prototypical oxygen (O2) sensitive arterial chemoreceptors, which, in response to lowered O2 tension (hypoxia), activate the respiratory centers to induce hyperventilation. It has been proposed that Olfr78 is a lactate receptor and that glomus cell activation by the increase in blood lactate mediates the hypoxic ventilatory response (HVR). However, this proposal has been challenged by several groups showing that Olfr78 is not a physiologically relevant lactate receptor and that the O2-based regulation of breathing is not affected in Olfr78 knockout mice. In another study, Olfr78 knockout mice were reported to have altered systemic and CB responses to mild hypoxia. These organismal phenotypes could result from pleiotropic effects of the constitutive Olfr78 knockout mutations in the various CB cell types and/or various organs where this gene is expressed. Therefore, to further characterize the functional role of Olfr78 in CB glomus cells, we here generated a conditional Olfr78 knockout mouse strain and then restricted the knockout to glomus cells and other catecholaminergic cells by crossing with a tyrosine hydroxylase-specific Cre driver strain (TH-Olfr78 KO mice). We find that TH-Olfr78 KO mice have a normal HVR. Interestingly, glomus cells of TH-Olfr78 KO mice exhibit molecular and electrophysiological alterations as well as a reduced dopamine content in secretory vesicles and neurosecretory activity. These functional characteristics resemble those of CB neuroblasts in wild-type mice. We suggest that, although Olfr78 is not essential for CB O2 sensing, activation of Olfr78-dependent pathways is required for the phenotypic specification of mature glomus cells.

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“…Interestingly, our analysis showed that Olfr59 (the rat equivalent to mouse Olfr78) gene was the only abundant Olfr member identified in the rat CB transcriptomic profile, highlighting the significance of G-protein signaling in different species. Peng et al [37] recently showed that redox modification of Olfr78 by H 2 S contributes to CB hypoxic sensing. In our study, Olfr59 gene expression increased significantly (> 2-fold) in adult CBs compared to neonates.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of Postnatal Rat Carotid Body Development

Wang,

Peng,

Kang

et al. 2024

Genes

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The carotid body (CB), located bilaterally at the carotid artery bifurcations, is the primary sensory organ for monitoring arterial blood O2 levels. Carotid bodies are immature at birth, exhibiting low sensitivity to hypoxia, and become more sensitive with maturation during the first few weeks of neonatal life. To understand the molecular basis for the postnatal developmental hypoxic responses of CB, we isolated CBs from 5-day and 21-day-old Sprague–Dawley rats and performed RNA sequencing, which allows comprehensive analysis of gene expression. Differentially expressed genes (DEGs) were generated using Edge R, while functional enrichment analysis was performed using gene-set enrichment analysis (GSEA). Analysis of RNA-Seq data showed 2604 DEGs of the total 12,696 genes shared between neonates and adults. Of the 2604 DEGs, 924 genes were upregulated, and 1680 genes were downregulated. Further analysis showed that genes related to oxidative phosphorylation (Ox/phos) and hypoxia-signaling pathways were significantly upregulated in neonatal CBs compared to adult CBs, suggesting a possible link to differential developmental hypoxic responses seen in CB. Genes related to cytokine signaling (INFγ and TNFα) and transcription factors (CREB and NFΚB) mediated pathways were enriched in adult CBs, suggesting that expression of these pathways may be linked to developmental regulation. The RNA-Seq results were verified by analyzing mRNA changes in selected genes by qRT-PCR. Our results of enrichment analysis of biological pathways offer valuable insight into CB hypoxic sensing responses related to the development process.

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Hypoxia sensing requires H ₂ S-dependent persulfidation of olfactory receptor 78

Cited by 10 publications

References 41 publications

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

Transcriptomic Analysis of Postnatal Rat Carotid Body Development

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Hypoxia sensing requires H 2 S-dependent persulfidation of olfactory receptor 78

Cited by 10 publications

References 41 publications

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Overexpression of olfactory receptor 78 ameliorates brain injury in cerebral ischaemia–reperfusion rats by activating Prkaca‐mediated cAMP/PKA‐MAPK pathway

Carotid Body Function in Tyrosine Hydroxylase Conditional Olfr78 Knockout Mice

Transcriptomic Analysis of Postnatal Rat Carotid Body Development

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Hypoxia sensing requires H ₂ S-dependent persulfidation of olfactory receptor 78