scholarly journals Molecular Mechanisms of Acute Oxygen Sensing by Arterial Chemoreceptor Cells. Role of Hif2α

2020 ◽  
Vol 11 ◽  
Author(s):  
Patricia Ortega-Sáenz ◽  
Alejandro Moreno-Domínguez ◽  
Lin Gao ◽  
José López-Barneo
Keyword(s):  
Carotid Body ◽  
Molecular Mechanisms ◽  
Experimental Tests ◽  
Mouse Genetics ◽  
Glomus Cells ◽  
Body Activity ◽  
Solid Foundation ◽  
Physical And Chemical ◽  
Membrane Signaling

Carotid body glomus cells are multimodal arterial chemoreceptors able to sense and integrate changes in several physical and chemical parameters in the blood. These cells are also essential for O2 homeostasis. Glomus cells are prototypical peripheral O2 sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation). The mechanisms underlying acute O2 sensing by glomus cells have been elusive. Using a combination of mouse genetics and single-cell optical and electrophysiological techniques, it has recently been shown that activation of glomus cells by hypoxia relies on the generation of mitochondrial signals (NADH and reactive oxygen species), which modulate membrane ion channels to induce depolarization, Ca2+ influx, and transmitter release. The special sensitivity of glomus cell mitochondria to changes in O2 tension is due to Hif2α-dependent expression of several atypical mitochondrial subunits, which are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. A mitochondrial-to-membrane signaling model of acute O2 sensing has been proposed, which explains existing data and provides a solid foundation for future experimental tests. This model has also unraveled new molecular targets for pharmacological modulation of carotid body activity potentially relevant in the treatment of highly prevalent medical conditions.

Possible Role of Coupling between Glomus Cells in Carotid Body Chemoreception

Neurosignals ◽  
1995 ◽  
Vol 4 (5) ◽  
pp. 263-270 ◽  
Author(s):  
C. Eyzaguirre ◽  
Verónica Abudara
Keyword(s):  
Carotid Body ◽  
Glomus Cells

scholarly journals Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia

2016 ◽  
Vol 310 (8) ◽  
pp. C629-C642 ◽  
Author(s):  
José López-Barneo ◽  
Patricia González-Rodríguez ◽  
Lin Gao ◽  
M. Carmen Fernández-Agüera ◽  
Ricardo Pardal ◽  
...  
Keyword(s):  
Carotid Body ◽  
Close Contact ◽  
Nerve Fibers ◽  
Whole Body ◽  
Adaptation To Hypoxia ◽  
Glomus Cells ◽  
Adaptive Processes ◽  
Cell Depolarization ◽  
Sensory Fibers

Oxygen (O2) is fundamental for cell and whole-body homeostasis. Our understanding of the adaptive processes that take place in response to a lack of O2 (hypoxia) has progressed significantly in recent years. The carotid body (CB) is the main arterial chemoreceptor that mediates the acute cardiorespiratory reflexes (hyperventilation and sympathetic activation) triggered by hypoxia. The CB is composed of clusters of cells (glomeruli) in close contact with blood vessels and nerve fibers. Glomus cells, the O2-sensitive elements in the CB, are neuron-like cells that contain O2-sensitive K+ channels, which are inhibited by hypoxia. This leads to cell depolarization, Ca2+ entry, and the release of transmitters to activate sensory fibers terminating at the respiratory center. The mechanism whereby O2 modulates K+ channels has remained elusive, although several appealing hypotheses have been postulated. Recent data suggest that mitochondria complex I signaling to membrane K+ channels plays a fundamental role in acute O2 sensing. CB activation during exposure to low Po2 is also necessary for acclimatization to chronic hypoxia. CB growth during sustained hypoxia depends on the activation of a resident population of stem cells, which are also activated by transmitters released from the O2-sensitive glomus cells. These advances should foster further studies on the role of CB dysfunction in the pathogenesis of highly prevalent human diseases.

scholarly journals CaV3.2 T-type Ca2+ channels in H2S-mediated hypoxic response of the carotid body

2015 ◽  
Vol 308 (2) ◽  
pp. C146-C154 ◽  
Author(s):  
Vladislav V. Makarenko ◽  
Ying-Jie Peng ◽  
Guoxiang Yuan ◽  
Aaron P. Fox ◽  
Ganesh K. Kumar ◽  
...  
Keyword(s):  
Carotid Body ◽  
Sensory Nerve ◽  
Wild Type ◽  
Glomus Cells ◽  
Arterial Blood ◽  
Carotid Bodies ◽  
Intracellular Ca ◽  
Ca2 Channels ◽  
Body Response

Arterial blood O2 levels are detected by specialized sensory organs called carotid bodies. Voltage-gated Ca2+ channels (VGCCs) are important for carotid body O2 sensing. Given that T-type VGCCs contribute to nociceptive sensation, we hypothesized that they participate in carotid body O2 sensing. The rat carotid body expresses high levels of mRNA encoding the α1H-subunit, and α1H protein is localized to glomus cells, the primary O2-sensing cells in the chemoreceptor tissue, suggesting that CaV3.2 is the major T-type VGCC isoform expressed in the carotid body. Mibefradil and TTA-A2, selective blockers of the T-type VGCC, markedly attenuated elevation of hypoxia-evoked intracellular Ca2+ concentration, secretion of catecholamines from glomus cells, and sensory excitation of the rat carotid body. Similar results were obtained in the carotid body and glomus cells from CaV3.2 knockout ( Cacna1h−/−) mice. Since cystathionine-γ-lyase (CSE)-derived H2S is a critical mediator of the carotid body response to hypoxia, the role of T-type VGCCs in H2S-mediated O2 sensing was examined. Like hypoxia, NaHS, a H2S donor, increased intracellular Ca2+ concentration and augmented carotid body sensory nerve activity in wild-type mice, and these effects were markedly attenuated in Cacna1h−/− mice. In wild-type mice, TTA-A2 markedly attenuated glomus cell and carotid body sensory nerve responses to hypoxia, and these effects were absent in CSE knockout mice. These results demonstrate that CaV3.2 T-type VGCCs contribute to the H2S-mediated carotid body response to hypoxia.

Role of mitochondria in the regulation of hypoxia-inducible factor-1α in the rat carotid body glomus cells

2005 ◽  
Vol 124 (1) ◽  
pp. 69-76 ◽  
Author(s):  
Santhosh M. Baby ◽  
Arijit Roy ◽  
Sukhamay Lahiri
Keyword(s):  
Carotid Body ◽  
Hypoxia Inducible Factor ◽  
Glomus Cells ◽  
Hypoxia Inducible Factor 1Α ◽  
Carotid Body Glomus Cells

scholarly journals CaV3.2 T-type Ca2+ channels mediate the augmented calcium influx in carotid body glomus cells by chronic intermittent hypoxia

2016 ◽  
Vol 115 (1) ◽  
pp. 345-354 ◽  
Author(s):  
Vladislav V. Makarenko ◽  
Gias U. Ahmmed ◽  
Ying-Jie Peng ◽  
Shakil A. Khan ◽  
Jayasri Nanduri ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Carotid Body ◽  
Protein Trafficking ◽  
Intermittent Hypoxia ◽  
Specific Inhibitor ◽  
Chronic Intermittent Hypoxia ◽  
Mrna Levels ◽  
Glomus Cells ◽  
Body Activity ◽  
Ros Scavenger

Chronic intermittent hypoxia (CIH) is a hallmark manifestation of sleep apnea. A heightened carotid body activity and the resulting chemosensory reflex mediate increased sympathetic nerve activity by CIH. However, the mechanisms underlying heightened carotid body activity by CIH are not known. An elevation of intracellular calcium ion concentration ([Ca2+]i) in glomus cells, the primary oxygen-sensing cells, is an essential step for carotid body activation by hypoxia. In the present study, we examined the effects of CIH on the glomus cell [Ca2+]i response to hypoxia and assessed the underlying mechanisms. Glomus cells were harvested from adult rats or wild-type mice treated with 10 days of either room air (control) or CIH (alternating cycles of 15 s of hypoxia and 5 min of room air; 9 episodes/h; 8 h/day). CIH-treated glomus cells exhibited an enhanced [Ca2+]i response to hypoxia, and this effect was absent in the presence of 2-(4-cyclopropylphenyl)- N-((1R)-1-[5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl]ethyl)acetamide (TTA-A2), a specific inhibitor of T-type Ca2+ channels, and in voltage-gated calcium channel, type 3.2 (CaV3.2), null glomus cells. CaV3.2 knockout mice exhibited an absence of CIH-induced hypersensitivity of the carotid body. CIH increased reactive oxygen species (ROS) levels in glomus cells. A ROS scavenger prevented the exaggerated TTA-A2-sensitive [Ca2+]i response to hypoxia. CIH had no effect on CaV3.2 mRNA levels. CIH augmented Ca2+ currents and increased CaV3.2 protein in plasma membrane fractions of human embryonic kidney-293 cells stably expressing CaV3.2, and either a ROS scavenger or brefeldin-A, an inhibitor of protein trafficking, prevented these effects. These findings suggest that CIH leads to an augmented Ca2+ influx via ROS-dependent facilitation of CaV3.2 protein trafficking to the plasma membrane.

scholarly journals The Role of the Transcription Factor Foxo3 in Hearing Maintenance: Informed Speculation on a New Player in the Cochlea

2016 ◽  
Vol 2016 ◽  
pp. 1-10
Author(s):  
Patricia M. White
Keyword(s):  
Hearing Loss ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Cell Types ◽  
Mouse Genetics ◽  
Molecular Response ◽  
Cellular Processes ◽  
Powerful Approach ◽  
Multiple Cell

Molecular genetics has proven to be a powerful approach for understanding early-onset hearing loss. Recent work in late-onset hearing loss uses mouse genetics to identify molecular mechanisms that promote the maintenance of hearing. One such gene, Foxo3, is ontologically involved in preserving mitochondrial function. Significant evidence exists to support the idea that mitochondrial dysfunction is correlated with and can be causal for hearing loss. Foxo3 is also ontologically implicated in driving the circadian cycle, which has recently been shown to influence the molecular response to noise damage. In this review, the molecular framework connecting these cellular processes is discussed in relation to the cellular pathologies observed in human specimens of late-onset hearing loss. In bringing these observations together, the possibility arises that distinct molecular mechanisms work in multiple cell types to preserve hearing. This diversity offers great opportunities to understand and manipulate genetic processes for therapeutic gain.

Acidic regulation of junction channels between glomus cells in the rat carotid body. Possible role of [Ca2+]i

2001 ◽  
Vol 916 (1-2) ◽  
pp. 50-60 ◽  
Author(s):  
Verónica Abudara ◽  
R.G. Jiang ◽  
C. Eyzaguirre
Keyword(s):  
Carotid Body ◽  
Glomus Cells

Physiology of the Carotid Body: From Molecules to Disease

2020 ◽  
Vol 82 (1) ◽  
pp. 127-149 ◽  
Author(s):  
Patricia Ortega-Sáenz ◽  
José López-Barneo
Keyword(s):  
Carotid Body ◽  
Molecular Mechanisms ◽  
Carotid Bifurcation ◽  
Sensory Cells ◽  
Glomus Cells ◽  
Cell Niche ◽  
And Function ◽  
Sensory Fibers ◽  
Acute Oxygen Sensing ◽  
Arterial Chemoreceptor

The carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation and has a well-recognized role in cardiorespiratory regulation. The CB contains neurosecretory sensory cells (glomus cells), which release transmitters in response to hypoxia, hypercapnia, and acidemia to activate afferent sensory fibers terminating in the respiratory and autonomic brainstem centers. Knowledge of the physiology of the CB has progressed enormously in recent years. Herein we review advances concerning the organization and function of the cellular elements of the CB, with emphasis on the molecular mechanisms of acute oxygen sensing by glomus cells. We introduce the modern view of the CB as a multimodal integrated metabolic sensor and describe the properties of the CB stem cell niche, which support CB growth during acclimatization to chronic hypoxia. Finally, we discuss the increasing medical relevance of CB dysfunction and its potential impact on the mechanisms of disease.

Fine Structure of Carotid Body: Normal and Anoxic Cats

1967 ◽  
Vol 25 ◽  
pp. 150-151
Author(s):  
Fadhil Al-Lami ◽  
R.G. Murray
Keyword(s):  
Fine Structure ◽  
Adrenal Medulla ◽  
Carotid Body ◽  
Uranyl Acetate ◽  
Lead Citrate ◽  
Glomus Cells ◽  
Sustentacular Cells ◽  
Carotid Bodies

Although the fine structure of the carotid body has been described in several recent reports, uncertainties remain, and the morphological effects of anoxia on the carotid body cells of the cat have never been reported. We have, therefore, studied the fine structure of the carotid body both in normal and severely anoxic cats, and to test the specificity of the effects, have compared them with the effects on adrenal medulla, kidney, and liver of the same animals. Carotid bodies of 50 normal and 15 severely anoxic cats (9% oxygen in nitrogen) were studied. Glutaraldehyde followed by OsO4 fixations, Epon 812 embedding, and uranyl acetate and lead citrate staining, were the technics employed.We have called the two types of glomus cells enclosed and enclosing cells. They correspond to those previously designated as chemoreceptor and sustentacular cells respectively (1). The enclosed cells forming the vast majority, are irregular in shape with many processes and occasional peripheral densities (Fig. 1).

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