Olfactory receptor 78 participates in carotid body response to a wide range of low O<sub>2</sub> levels but not severe hypoxia

Peng, Yingjie; Gridina, Anna; Wang, Benjamin; Nanduri, Jayasri; Fox, Aaron P.; Prabhakar, Nanduri R.

doi:10.1152/jn.00075.2020

Cited by 25 publications

(34 citation statements)

References 25 publications

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“…It has also been reported that lactate activates the CB by means of binding to an atypical olfactory receptor (Olfr78) that is highly expressed in the CB's chemoreceptor (or glomus) cells 28 . This latter proposal was disregarded because the findings could not be reproduced by others [29][30][31][32] . Nonetheless, in preliminary studies, we found that single Olfr78-deficient glomus cells are indeed directly activated by lactate 31 .…”

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confidence: 99%

Lactate sensing mechanisms in arterial chemoreceptor cells

et al. 2021

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Classically considered a by-product of anaerobic metabolism, lactate is now viewed as a fundamental fuel for oxidative phosphorylation in mitochondria, and preferred over glucose by many tissues. Lactate is also a signaling molecule of increasing medical relevance. Lactate levels in the blood can increase in both normal and pathophysiological conditions (e.g., hypoxia, physical exercise, or sepsis), however the manner by which these changes are sensed and induce adaptive responses is unknown. Here we show that the carotid body (CB) is essential for lactate homeostasis and that CB glomus cells, the main oxygen sensing arterial chemoreceptors, are also lactate sensors. Lactate is transported into glomus cells, leading to a rapid increase in the cytosolic NADH/NAD+ ratio. This in turn activates membrane cation channels, leading to cell depolarization, action potential firing, and Ca2+ influx. Lactate also decreases intracellular pH and increases mitochondrial reactive oxygen species production, which further activates glomus cells. Lactate and hypoxia, although sensed by separate mechanisms, share the same final signaling pathway and jointly activate glomus cells to potentiate compensatory cardiorespiratory reflexes.

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confidence: 99%

Lactate sensing mechanisms in arterial chemoreceptor cells

et al. 2021

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“…3c, d, Fig. S6c, d), suggesting that strong ETC inhibition can still trigger sensory responses in Higd1c 1-1 -/- glomus cells like other mutants with defects in CB oxygen sensing ( 20, 21 ). Together, these results show that HIGD1C contributes specifically to glomus cell responses to hypoxia involved in oxygen sensing.…”

Section: Higd1c Mediates Cb Sensory and Metabolic Responses To Hypoxiamentioning

confidence: 85%

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

Timón‐Gómez

Scharr

Wong

et al. 2021

Preprint

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The carotid body (CB) is the major chemoreceptor for blood oxygen in the control of ventilation in mammals, contributing to physiological adaptation to high altitude, pregnancy, and exercise, and its hyperactivity is linked to chronic conditions such as sleep-disorder breathing, hypertension, chronic heart failure, airway constriction, and metabolic syndrome. Upon acute hypoxia (PO2=100 mmHg to <80 mmHg), K+ channels on CB glomus cells are inhibited, causing membrane depolarization to trigger Ca+2 influx and neurotransmitter release that stimulates afferent nerves. A longstanding model proposes that the CB senses hypoxia through atypical mitochondrial electron transport chain (ETC) metabolism that is more sensitive to decreases in oxygen than other tissues. This model is supported by observations that ETC inhibition by pharmacology and gene knockout activates CB sensory activity and that smaller decreases in oxygen concentration inhibit ETC activity in CB cells compared to other cells. Determining the composition of atypical ETC subunits in the CB and their specific activities is essential to delineate molecular mechanisms underlying the mitochondrial hypothesis of oxygen sensing. Here, we identify HIGD1C, a novel hypoxia inducible gene domain factor isoform, as an ETC Complex IV (CIV) protein highly and selectively expressed in glomus cells that mediates acute oxygen sensing by the CB. We demonstrate that HIGD1C negatively regulates oxygen consumption by CIV and acts with the hypoxia-induced CIV subunit COX4I2 to enhance the sensitivity of CIV to hypoxia, constituting an important component of mitochondrial oxygen sensing in the CB. Determining how HIGD1C and other atypical CIV proteins expressed in the CB work together to confer exquisite oxygen sensing to the ETC will help us better understand how tissue- and condition-specific CIV subunits contribute to physiological function and disease and allow us to potentially target these proteins to treat chronic diseases characterized by CB dysfunction.

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“…Olfr78 is known to be expressed in the renal JGA, as well as the smooth muscle cells of the peripheral vasculature (Pluznick et al, 2013 ). Additionally, Olfr78 expression has been reported in colonic enteroendocrine cells, autonomic ganglia, and the carotid body (Chang et al, 2015 ; Fleischer et al, 2015 ; Weber et al, 2002 ), although Olfr78’s role in the carotid body has been a disputed topic (Chang et al, 2015 ; Peng et al, 2020 ; Torres‐Torrelo et al, 2018 ). Expression of Olfr78 in this context may be playing a role in the bradycardia we observe under salt stress.…”

Section: Discussionmentioning

confidence: 99%

Olfactory receptor 78 modulates renin but not baseline blood pressure

Poll

Gupta

et al. 2021

Physiol Rep

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Olfactory receptors (ORs) are the largest family of Gprotein coupled receptors (GPCRs), with nearly 350 genes in humans (Malnic et al., 2004) and nearly 1000 genes in mice (Godfrey et al., 2004). While they were initially characterized as specialized chemosensors in the nose, ORs are also expressed in a wide range of tissues where they play functional roles (Griffin et al., 2009;Spehr et al., 2003), including in the kidney (Pluznick et al., 2009). Although most murine ORs do not have a clear human ortholog, Olfactory receptor 78 (Olfr78) is one of only three murine genes to have a clear ortholog across 13 placental mammals, including humans (Niimura et al., 2014). In a prior study, we reported that Olfr78 localizes to both vascular smooth muscle cells and to the juxtaglomerular apparatus (JGA) of the kidney, where it plays a role in renin release (Pluznick et al., 2013). Both Olfr78 and its human ortholog OR51E2 respond to the short chain fatty acids (SCFAs) acetate and propionate

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Olfactory receptor 78 participates in carotid body response to a wide range of low O₂ levels but not severe hypoxia

Cited by 25 publications

References 25 publications

Lactate sensing mechanisms in arterial chemoreceptor cells

Lactate sensing mechanisms in arterial chemoreceptor cells

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

Olfactory receptor 78 modulates renin but not baseline blood pressure

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Olfactory receptor 78 participates in carotid body response to a wide range of low O2 levels but not severe hypoxia

Cited by 25 publications

References 25 publications

Lactate sensing mechanisms in arterial chemoreceptor cells

Lactate sensing mechanisms in arterial chemoreceptor cells

A mitochondrial electron transport chain with atypical subunit composition confers oxygen sensitivity to a mammalian chemoreceptor

Olfactory receptor 78 modulates renin but not baseline blood pressure

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Olfactory receptor 78 participates in carotid body response to a wide range of low O₂ levels but not severe hypoxia