The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article.

Peripheral Chemoreceptors: Function and Plasticity of the Carotid Body

The control of breathing depends critically on sensory inputs to the central pattern generator of the brainstem, arising from peripheral arterial chemoreceptors located principally in the carotid bodies (CBs). The CB receptors, i.e. glomus or type I cells, are excited by chemical stimuli in arterial blood, particularly hypoxia, hypercapnia, acidosis and low glucose, which initiate corrective reflex cardiorespiratory and cardiovascular adjustments. Type I cells occur in clusters and are innervated by petrosal afferent fibres. Synaptic specializations (both chemical and electrical) occur between type I cells and petrosal terminals, and between neighbouring type I cells. This, together with the presence of a wide array of neurotransmitters and neuromodulators linked to both ionotropic and metabotropic receptors, allows for a complex modulation of CB sensory output. Studies in several laboratories over the last 20 years have provided much insight into the transduction mechanisms. More recent studies, aided by the development of a co-culture model of the rat CB, have shed light on the role of neurotransmitters and neuromodulators in shaping the afferent response. This review highlights some of these developments, which have contributed to our current understanding of information processing at CB chemoreceptors.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/expphysiol.2009.049312

Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors.

Maintenance of homeostasis in the respiratory and cardiovascular systems depends on reflexes that are initiated at specialized peripheral chemoreceptors that sense changes in the chemical composition of arterial blood. In mammals, the bilaterally-paired carotid bodies (CBs) are the main peripheral chemoreceptor organs that are richly vascularized and are strategically located at the carotid bifurcation. The CBs contribute to the maintenance of O2, CO2/H+, and glucose homeostasis and have attracted much clinical interest because hyperactivity in these organs is associated with several pathophysiological conditions including sleep apnea, obstructive lung disease, heart failure, hypertension, and diabetes. In response to a decrease in O2 availability (hypoxia) and elevated CO2/H+ (acid hypercapnia), CB receptor type I (glomus) cells depolarize and release neurotransmitters that stimulate apposed chemoafferent nerve fibers. The central projections of those fibers in turn activate cardiorespiratory centers in the brainstem, leading to an increase in ventilation and sympathetic drive that helps restore blood PO2 and protect vital organs, e.g., the brain. Significant progress has been made in understanding how neurochemicals released from type I cells such as ATP, adenosine, dopamine, 5-HT, ACh, and angiotensin II help shape the CB afferent discharge during both normal and pathophysiological conditions. However, type I cells typically occur in clusters and in addition to their sensory innervation are ensheathed by the processes of neighboring glial-like, sustentacular type II cells. This morphological arrangement is reminiscent of a "tripartite synapse" and emerging evidence suggests that paracrine stimulation of type II cells by a variety of CB neurochemicals may trigger the release of "gliotransmitters" such as ATP via pannexin-1 channels. Further, recent data suggest novel mechanisms by which dopamine, acting via D2 receptors (D2R), may inhibit action potential firing at petrosal nerve endings. This review will update current ideas concerning the presynaptic and postsynaptic mechanisms that underlie chemosensory processing in the CB. Paracrine signaling pathways will be highlighted, and particularly those that allow the glial-like type II cells to participate in the integrated sensory response during exposures to chemostimuli, including acute and chronic hypoxia.

/pdf/sensory-processing-and-integration-at-the-carotid-body-4m5sudvh1i.pdf

Sensory Processing and Integration at the Carotid Body Tripartite Synapse: Neurotransmitter Functions and Effects of Chronic Hypoxia

Mammalian carotid bodies (CB) are chemosensory organs that mediate compensatory cardiorespiratory reflexes in response to low blood PO2 (hypoxemia) and elevated CO2/H+ (acid hypercapnia). The chemo...

Role of glial-like type II cells as paracrine modulators of carotid body chemoreception

The carotid body (CB) is an important organ located at the carotid bifurcation that constantly monitors the blood supplying the brain. During hypoxia, the CB immediately triggers an alarm in the form of nerve impulses sent to the brain. This activates protective reflexes including hyperventilation, tachycardia and vasoconstriction, to ensure blood and oxygen delivery to the brain and vital organs. However, in certain conditions, including obstructive sleep apnea, heart failure and essential/spontaneous hypertension, the CB becomes hyperactive, promoting neurogenic hypertension and arrhythmia. G-protein-coupled receptors (GPCRs) are very highly expressed in the CB and have key roles in mediating baseline CB activity and hypoxic sensitivity. Here, we provide a brief overview of the numerous GPCRs that are expressed in the CB, their mechanism of action and downstream effects. Furthermore, we will address how these GPCRs and signaling pathways may contribute to CB hyperactivity and cardiovascular and respiratory disease. GPCRs are a major target for drug discovery development. This information highlights specific GPCRs that could be targeted by novel or existing drugs to enable more personalized treatment of CB-mediated cardiovascular and respiratory disease.

/pdf/g-protein-coupled-receptor-gpcr-signaling-in-the-carotid-4bnt38t3v0.pdf

G-Protein-Coupled Receptor (GPCR) Signaling in the Carotid Body: Roles in Hypoxia and Cardiovascular and Respiratory Disease.

Evidence for functional, inhibitory, histamine H3 receptors in rat carotid body Type I cells.

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Evidence for functional, inhibitory, histamine H3 receptors in rat carotid body Type I cells.