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

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.

Keywords: G-protein; GPCR; carotid body; drug-discovery; hypertension; hypoxia.

Figure 1

Schematic illustration of ecto-5′-nucleotidase (CD73)-mediated adenosine generation and signaling in the carotid body (CB). During normoxia/hypoxia, ATP released as a neurotransmitter can be converted to adenosine by the action of ecto-nucleosidetriphosphate diphosphohydrolase (CD39) and CD73. Alternatively, ATP can be converted to adenosine in the type I cell and released via the equilibrative nucleoside transporter (ENT). Adenosine binds to A₂-receptors on the pre- and post-synaptic membrane to increase baseline activity and overall hypoxic sensitivity. Filled lines denote purinergic signaling, dashed lines denote ion flow.

Figure 2

Schematic illustration of adrenaline activation of the carotid body (CB) during hypoglycemia. When blood glucose decreases, this is sensed in the brainstem and leads to a reflex increase in adrenaline release from the adrenal medulla. β-adrenoceptors in type 1 cells will be activated by adrenaline. This activation will lead to an increase in CO₂ sensitivity, neurotransmitter release and an increase in ventilation. The elevation in ventilation matches the increase in metabolic rate and CO₂ generation (VCO₂), such that the overall partial pressure of arterial CO₂ (P_aCO₂) and pH remain constant. The ? denotes that the signaling mechanism linking increased CO₂ sensitivity with enhanced neurotransmitter release is still unknown. Lines with arrows denote signaling pathways. Lines with circles and chevrons denote efferent neurons.

Figure 3

Summary of G-protein signaling in the carotid body type I cell. The activation of G_q-protein-coupled receptors (Green) activates phospholipase C (PLC), which in turn leads to the formation of both inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ will bind to the endoplasmic reticulum (ER), causing ER Ca²⁺ efflux. DAG will activate protein kinase C (PKC). The activation of G_s-protein-coupled receptors (Blue) will activate transmembrane adenylyl cyclase (tmAC), leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) production, which will activate protein kinase A (PKA). The activation of pituitary adenylate cyclase-activating polypeptide type 1 (PAC₁) and endothelin (ET) receptors (Pink) could activate both G_q and G_s mechanisms. Stimulation of G_i-protein-coupled receptors (Gray) predominantly by dopamine will inhibit tmAC activity, which in turn decreases cAMP. The overall balance between the concentration of external ligands and the extent of activation of each of the G_s, G_i and G_q pathways is capable of acutely fine-tuning the type I cell hypoxic sensitivity. Many of these receptors and signaling pathways are also involved in physiological and pathological carotid body adaptation. The dashed circle identifies the position of the CB and type I cells at the carotid bifurcation. Dashed lines denote receptor activation linking to specific downstream enzymes. Filled lines denote further downstream or upstream signaling cascades.