Constitutive Expression of Hif2α Confers Acute O Sensitivity to Carotid Body Glomus Cells.

Acute oxygen (O) sensing and adaptation to hypoxia are essential for physiological homeostasis. The prototypical acute O sensing organ is the carotid body, which contains chemosensory glomus cells expressing O-sensitive K channels. Inhibition of these channels during hypoxia leads to cell depolarization, transmitter release, and activation of afferent sensory fibers terminating in the brain stem respiratory and autonomic centers.

Protection and Repair of the Nigrostriatal Pathway with Stem-Cell-Derived Carotid Body Glomus Cell Transplants in Chronic MPTP Parkinsonian Model.

Antiparkinsonian carotid body (CB) cell therapy has been proven to be effective in rodent and nonhuman primate models of Parkinson's disease (PD), exerting trophic protection and restoration of the dopaminergic nigrostriatal pathway. These neurotrophic actions are mediated through the release of high levels of glial-cell-line-derived neurotrophic factor (GDNF) by the CB transplant. Pilot clinical trials have also shown that CB autotransplantation can improve motor symptoms in PD patients, although its effectiveness is affected by the scarcity of the grafted tissue.

Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice.

The hypoxic ventilatory response (HVR) is a life-saving reflex, triggered by the activation of chemoreceptor glomus cells in the carotid body (CB) connected with the brainstem respiratory center. The molecular mechanisms underlying glomus cell acute oxygen (O) sensing are unclear. Genetic disruption of mitochondrial complex I (MCI) selectively abolishes the HVR and glomus cell responsiveness to hypoxia.

Rearrangement of cell types in the rat carotid body neurogenic niche induced by chronic intermittent hypoxia.

The carotid body (CB) is a prototypical acute oxygen (O )-sensing organ that mediates reflex hyperventilation and increased cardiac output in response to hypoxaemia. CB overactivation, secondary to the repeated stimulation produced by the recurrent episodes of intermittent hypoxia, is believed to contribute to the pathogenesis of sympathetic hyperactivity present in sleep apnoea patients. Although CB functional plasticity induced by chronic intermittent hypoxia (CIH) has been demonstrated, the underlying mechanisms are not fully elucidated.

Oxygen regulation of breathing is abolished in mitochondrial complex III-deficient arterial chemoreceptors.

Acute oxygen (O) sensing is essential for adaptation of organisms to hypoxic environments or medical conditions with restricted exchange of gases in the lung. The main acute O-sensing organ is the carotid body (CB), which contains neurosecretory chemoreceptor (glomus) cells innervated by sensory fibers whose activation by hypoxia elicits hyperventilation and increased cardiac output. Glomus cells have mitochondria with specialized metabolic and electron transport chain (ETC) properties.

Mitochondrial Redox Signaling in O-Sensing Chemoreceptor Cells.

Acute responses to hypoxia are essential for the survival of mammals. The carotid body (CB), the main arterial chemoreceptor, contains glomus cells with oxygen (O)-sensitive K channels, which are inhibited during hypoxia to trigger adaptive cardiorespiratory reflexes. In this review, recent advances in molecular mechanisms of acute O sensing in CB glomus cells are discussed, with a special focus on the signaling role of mitochondria through regulating cellular redox status.

Mitochondrial acute oxygen sensing and signaling.

Oxygen (O) is essential for life and therefore the supply of sufficient O to the tissues is a major physiological challenge. In mammals, a deficit of O (hypoxia) triggers rapid cardiorespiratory reflexes (e.g.

Lactate sensing mechanisms in arterial chemoreceptor cells.

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.

Using redox-sensitive fluorescent probes to record real-time reactive oxygen species production in cells from mouse carotid body slices.

Reactive oxygen species (ROS) are important signaling molecules for physiologic processes such as acute response to hypoxia. However, reliable real-time ROS measurement in cells has been a long-standing methodological challenge. Here, we present a protocol to record acute changes in ROS production in sensory cells from mouse carotid body (CB) slices using redox-sensitive green fluorescent protein probes and microfluorimetry.

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

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 O homeostasis. Glomus cells are prototypical peripheral O sensors necessary to detect hypoxemia and to elicit rapid compensatory responses (hyperventilation and sympathetic activation).

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

Acute cardiorespiratory responses to O deficiency are essential for physiological homeostasis. The prototypical acute O-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 O tension modulate ion channels has remained elusive.

Physiology of the Carotid Body: From Molecules to Disease.

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.

Acute oxygen sensing-Role of metabolic specifications in peripheral chemoreceptor cells.

Acute oxygen sensing is essential for humans under hypoxic environments or pathologic conditions. This is achieved by the carotid body (CB), the key arterial chemoreceptor, along with other peripheral chemoreceptor organs, such as the adrenal medulla (AM). Although it is widely accepted that inhibition of K channels in the plasma membrane of CB cells during acute hypoxia results in the activation of cardiorespiratory reflexes, the molecular mechanisms by which the hypoxic signal is detected to modulate ion channel activity are not fully understood.

Acute O Sensing: Role of Coenzyme QH/Q Ratio and Mitochondrial ROS Compartmentalization.

Acute O sensing by peripheral chemoreceptors is essential for mammalian homeostasis. Carotid body glomus cells contain O-sensitive ion channels, which trigger fast adaptive cardiorespiratory reflexes in response to hypoxia. O-sensitive cells have unique metabolic characteristics that favor the hypoxic generation of mitochondrial complex I (MCI) signaling molecules, NADH and reactive oxygen species (ROS), which modulate membrane ion channels.

HIF-2α is essential for carotid body development and function.

Mammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2α, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body.

Testing Acute Oxygen Sensing in Genetically Modified Mice: Plethysmography and Amperometry.

Monitoring responsiveness to acute hypoxia of whole animals and single cells is essential to investigate the nature of the mechanisms underlying oxygen (O) sensing. Here we describe the protocols followed in our laboratory to evaluate the ventilatory response to hypoxia in normal and genetically modified animals. We also describe the amperometric technique used to monitor single-cell catecholamine release from chemoreceptor cells in carotid body and adrenal medulla slices.

Monitoring Functional Responses to Hypoxia in Single Carotid Body Cells.

The carotid body is the main arterial chemoreceptor in mammals that mediates the cardiorespiratory reflexes activated by acute hypoxia. Here we describe the protocols followed in our laboratory to study responsiveness to hypoxia of single, enzymatically dispersed, glomus cells monitored by microfluorimetry and the patch-clamp technique.

Gene expression analyses reveal metabolic specifications in acute O -sensing chemoreceptor cells.

Key Points: Glomus cells in the carotid body (CB) and chromaffin cells in the adrenal medulla (AM) are essential for reflex cardiorespiratory adaptation to hypoxia. However, the mechanisms whereby these cells detect changes in O tension are poorly understood. The metabolic properties of acute O -sensing cells have been investigated by comparing the transcriptomes of CB and AM cells, which are O -sensitive, with superior cervical ganglion neurons, which are practically O -insensitive.

Redox signaling in acute oxygen sensing.

Acute oxygen (O) sensing is essential for individuals to survive under hypoxic conditions. The carotid body (CB) is the main peripheral chemoreceptor, which contains excitable and O-sensitive glomus cells with O-regulated ion channels. Upon exposure to acute hypoxia, inhibition of K channels is the signal that triggers cell depolarization, transmitter release and activation of sensory fibers that stimulate the brainstem respiratory center to produce hyperventilation.

Selective accumulation of biotin in arterial chemoreceptors: requirement for carotid body exocytotic dopamine secretion.

Key Points: Biotin, a vitamin whose main role is as a coenzyme for carboxylases, accumulates at unusually large amounts within cells of the carotid body (CB). In biotin-deficient rats biotin rapidly disappears from the blood; however, it remains at relatively high levels in CB glomus cells. The CB contains high levels of mRNA for SLC5a6, a biotin transporter, and SLC19a3, a thiamine transporter regulated by biotin.