Abstract
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.
Highlights
The carotid body (CB) is a vital sensory organ, located near the carotid bifurcation, that constantly monitors blood supplying the brain [1]
Despite being in a different experimental setting, we propose that lactate may have an additional role as an alternative energy source, independent of Olfr78, similar to that seen in the central nervous system (CNS) and peripheral nerves [52,53]
Hypoxia induces a significant increase in 5-HT release from type I cells in chronic intermittent hypoxia (CIH)-treated animals, which in turn leads to an increase in protein kinase C (PKC) activity and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase 2-derived reactive oxygen species (ROS) generation, which is suggested to cause persistent chemoafferent hyperactivity [115]
Summary
The carotid body (CB) is a vital sensory organ, located near the carotid bifurcation, that constantly monitors blood supplying the brain [1]. The CB is stimulated by acute hypoxia, upon which it rapidly activates vital cardiovascular and respiratory reflexes, including peripheral vasoconstriction, elevated heart rate and increased breathing [2]. These ensure that sufficient blood-oxygen is delivered to the brain to support survival. Activation of Gαs will lead to transmembrane adenylyl cyclase (tmAC) stimulation, which in turn leads to an increase in intracellular cyclic adenosine monophosphate (cAMP). The activation of Gαq stimulates phospholipase C (PLC), leading to the production of diacylglycerol (DAG) and inositol trisphosphate (IP3), which can modify [Ca2+]i, protein kinase activity, ion channel function and potentially reactive oxygen species (ROS) generation [1]. The aim of this review is to briefly explore the role of the major GPCRs and associated ligands in the CB, both in mediating normal CB function, hypoxic sensitivity and CB hyperactivity
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