Acute O2 sensing through HIF2α-dependent expression of atypical cytochrome oxidase subunits in arterial chemoreceptors

2019 ◽  
Vol 13 (615) ◽  
pp. eaay9452 ◽  
Author(s):  
Alejandro Moreno-Domínguez ◽  
Patricia Ortega-Sáenz ◽  
Lin Gao ◽  
Olalla Colinas ◽  
Paula García-Flores ◽  
...  
Keyword(s):  
Ion Channels ◽  
Carotid Body ◽  
Acute Hypoxia ◽  
Mechanistic Explanation ◽  
Nerve Fibers ◽  
Adaptive Responses ◽  
Glomus Cells ◽  
Adult Mice ◽  
Genes Encoding ◽  
Regulation Of Breathing

Acute cardiorespiratory responses to O2 deficiency are essential for physiological homeostasis. The prototypical acute O2-sensing organ is the carotid body, which contains glomus cells expressing K+ channels whose inhibition by hypoxia leads to transmitter release and activation of nerve fibers terminating in the brainstem respiratory center. The mechanism by which changes in O2 tension modulate ion channels has remained elusive. Glomus cells express genes encoding HIF2α (Epas1) and atypical mitochondrial subunits at high levels, and mitochondrial NADH and reactive oxygen species (ROS) accumulation during hypoxia provides the signal that regulates ion channels. We report that inactivation of Epas1 in adult mice resulted in selective abolition of glomus cell responsiveness to acute hypoxia and the hypoxic ventilatory response. Epas1 deficiency led to the decreased expression of atypical mitochondrial subunits in the carotid body, and genetic deletion of Cox4i2 mimicked the defective hypoxic responses of Epas1-null mice. These findings provide a mechanistic explanation for the acute O2 regulation of breathing, reveal an unanticipated role of HIF2α, and link acute and chronic adaptive responses to hypoxia.

scholarly journals Roles of Ion Channels in Carotid Body Chemotransmission of Acute Hypoxia.

1999 ◽  
Vol 49 (3) ◽  
pp. 213-228 ◽  
Author(s):  
Machiko SHIRAHATA ◽  
James S.K. SHAM
Keyword(s):  
Ion Channels ◽  
Carotid Body ◽  
Acute Hypoxia

Abstract 956: Acid-Sensing Ion Channels (ASICs) Contribute to Transduction of Extracellular Acidosis in Rat Carotid Body Glomus Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Zhi-Yong Tan ◽  
Yongjun Lu ◽  
Carol A Whiteis ◽  
Christopher J Benson ◽  
Mark W Chapleau ◽  
...  
Keyword(s):  
Ion Channels ◽  
Carotid Body ◽  
Bathing Solution ◽  
Ph Sensing ◽  
Pipette Solution ◽  
Glomus Cells ◽  
Extracellular Acidosis ◽  
Task Channels ◽  
Carotid Body Chemoreceptors ◽  
Carotid Body Glomus Cells

The molecular mechanism of pH sensing by chemoreceptors is not clear, although it had been proposed to be mediated by a drop in intracellular pH of carotid body glomus cells, which inhibits a K + current. Recently, pH-sensitive ion channels have been described in glomus cells that respond directly to extracellular acidosis. In this study, we investigated the possible molecular mechanisms of carotid body pH-sensing by recording the responses of glomus cells isolated from rat carotid body to rapid changes in extracellular pH using whole-cell patch-clamping technique. Extracellular acidosis evoked transient inward currents in glomus cells that were evident at pH 7.0 and half-activated (pH 50) at 6.3. The current had the characteristics of ASICs. It averaged 40.7±15.7 pA (n=5) at pH 5.0 and was blocked by the ASIC channel blocker amiloride (200 μm) to 2.5±1.6 pA. Na + free bathing solution eliminated the current and a Ca 2+ free buffer enhanced (P<0.05) the current at pH 6.0 from 18.5±2.2 to 86.0±12.5 pA (n=5). Enhancement of the current was also seen with the addition of lactate. In the current clamp mode extracellular acidosis evoked both a transient and sustained depolarization. The initial transient component at pH 6.0 averaged 18.2±2.6 mV and was blocked by amiloride to 2.1±2.1 mV supporting the contribution of ASICs. However, the sustained depolarization was not blocked by amiloride but was eliminated by removal of K + from the pipette solution which reduced significantly intracellular K + . This sustained depolarization was partially blocked by the TASK channels blockers anandamide (from 14.9±1.6 mV to 9.3±2.2 mV at pH 6.0, n=5) and quinidine (from 27.5±2.2 mV to 11.3±2.3 mV at pH 6.0, n=3). The results provide the first evidence that ASICs may contribute to chemotransduction of low pH by carotid body chemoreceptors, and that extracellular acidosis directly activates carotid body chemoreceptors through both ASIC and TASK channels.

scholarly journals Expression of Tandem P Domain K+ Channel, TREK-1, in the Rat Carotid Body

2006 ◽  
Vol 54 (4) ◽  
pp. 467-472 ◽  
Author(s):  
Y. Yamamoto ◽  
K. Taniguchi
Keyword(s):  
In Situ Hybridization ◽  
Mrna Expression ◽  
Carotid Body ◽  
Nerve Fibers ◽  
K Channel ◽  
Membrane Excitability ◽  
Rt Pcr ◽  
Glomus Cells ◽  
Afferent Nerve Endings

TREK-1 is one of the important potassium channels for regulating membrane excitability. To examine the distribution of TREK-1 in the rat carotid body, we performed RT-PCR for mRNA expression and in situ hybridization and immunohistochemistry for tissue distribution of TREK-1. RT-PCR detected mRNA expression of TREK-1 in the carotid body. Furthermore, in situ hybridization revealed the localization of TREK-1 mRNA in the glomus cells. TREK-1 immunoreactivity was mainly distributed in the glomus cells and nerve fibers in the carotid body. TREK-1 may modulate potassium current of glomus cells and/or afferent nerve endings in the rat carotid body.

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.

Hypoxia transduction by carotid body chemoreceptors in mice lacking dopamine D2 receptors

2007 ◽  
Vol 103 (4) ◽  
pp. 1269-1275 ◽  
Author(s):  
J. Prieto-Lloret ◽  
D. F. Donnelly ◽  
A. J. Rico ◽  
R. Moratalla ◽  
C. González ◽  
...  
Keyword(s):  
Carotid Body ◽  
Acute Hypoxia ◽  
Genetically Engineered ◽  
Afferent Nerve ◽  
Severe Hypoxia ◽  
Glomus Cells ◽  
Genetically Engineered Mice ◽  
Carotid Body Chemoreceptors ◽  
Mild Hypoxia

Hypoxia-induced dopamine (DA) release from carotid body (CB) glomus cells and activation of postsynaptic D2 receptors have been proposed to play an important role in the neurotransmission process between the glomus cells and afferent nerve endings. To better resolve the role of D2 receptors, we examined afferent nerve activity, catecholamine content and release, and ventilation of genetically engineered mice lacking D2 receptors (D2−/− mice). Single-unit afferent nerve activities of D2−/− mice in vitro were significantly reduced by 45% and 25% compared with wild-type (WT) mice during superfusion with saline equilibrated with mild hypoxia (Po2 ∼50 Torr) or severe hypoxia (Po2 ∼20 Torr), respectively. Catecholamine release in D2−/− mice was enhanced by 125% in mild hypoxia and 75% in severe hypoxia compared with WT mice, and the rate of rise was increased in D2−/− mice. We conclude that CB transduction of hypoxia is still present in D2−/− mice, but the response magnitude is reduced. However, the ventilatory response to acute hypoxia is maintained, perhaps because of an enhanced processing of chemoreceptor input by brain stem respiratory nuclei.

scholarly journals Acid-Sensing Ion Channels Contribute to Transduction of Extracellular Acidosis in Rat Carotid Body Glomus Cells

2007 ◽  
Vol 101 (10) ◽  
pp. 1009-1019 ◽  
Author(s):  
Zhi-Yong Tan ◽  
Yongjun Lu ◽  
Carol A. Whiteis ◽  
Christopher J. Benson ◽  
Mark W. Chapleau ◽  
...  
Keyword(s):  
Ion Channels ◽  
Carotid Body ◽  
Glomus Cells ◽  
Extracellular Acidosis ◽  
Acid Sensing Ion Channels ◽  
Carotid Body Glomus Cells

Inhibition of rat carotid body glomus cells TASK-like channels by acute hypoxia is enhanced by chronic intermittent hypoxia

2013 ◽  
Vol 185 (3) ◽  
pp. 600-607 ◽  
Author(s):  
Fernando C. Ortiz ◽  
Rodrigo Del Rio ◽  
German Ebensperger ◽  
Victor R. Reyes ◽  
Julio Alcayaga ◽  
...  
Keyword(s):  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Acute Hypoxia ◽  
Chronic Intermittent Hypoxia ◽  
Glomus Cells ◽  
Carotid Body Glomus Cells

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).

Extraction of Auditory Information by Modulation of Neuronal Ion Channels

2018 ◽  
pp. 272-300
Author(s):  
Leonard K. Kaczmarek
Keyword(s):  
Ion Channels ◽  
Neuronal Firing ◽  
Auditory Information ◽  
Auditory Neurons ◽  
Complex Sound ◽  
Medial Nucleus ◽  
Rapid Changes ◽  
Genes Encoding ◽  
Kinetics Of ◽  
Trapezoid Body

All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.

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