Purinergic signalling mediates bidirectional crosstalk between chemoreceptor type I and glial‐like type II cells of the rat carotid body

Abstract

Key pointsr Carotid body chemoreceptors are organized in clusters containing receptor type I and contiguous glial-like type II cells.r While type I cells depolarize and release ATP during chemostimulation, the role of type II cells which express purinergic P2Y2 receptors (P2Y2Rs) and ATP-permeable pannexin-1 (Panx-1) channels, is unclear. r We propose that reciprocal crosstalk between type I and type II cells contributes to sensory processing in the carotid body via purinergic signalling pathways. AbstractThe mammalian carotid body (CB) is excited by blood-borne stimuli including hypoxia and acid hypercapnia, leading to respiratory and cardiovascular reflex responses. This chemosensory organ consists of innervated clusters of receptor type I cells, ensheathed by processes of adjacent glial-like type II cells. ATP is a major excitatory neurotransmitter released from type I cells and type II cells express purinergic P2Y2 receptors (P2Y2Rs), the activation of which leads to the opening of ATP-permeable, pannexin-1 (Panx-1) channels. While these properties support crosstalk between type I and type II cells during chemotransduction, direct evidence is lacking. To address this, we first exposed isolated rat chemoreceptor clusters to acute hypoxia, isohydric hypercapnia, or the depolarizing stimulus high K + , and monitored intracellular [Ca 2+ ] using Fura-2. As expected, these stimuli induced intracellular [Ca 2+ ] elevations ( [Ca 2+ ] i ) in type I cells. Interestingly, however, there was often a delayed, secondary [Ca 2+ ] i in nearby type II cells that was reversibly inhibited by the P2Y2R antagonist suramin, or by the nucleoside hydrolase apyrase. By contrast, type II cell stimulation with the P2Y2R agonist uridine-5 -triphosphate (100 μM) often led to a delayed, secondary [Ca 2+ ] i response in nearby type I cells that was reversibly inhibited by the Panx-1 blocker carbenoxolone (5 μM). This [Ca 2+ ] i response was also strongly inhibited by blockers of either the adenosine A 2A receptor (SCH 58261) or of the 5 -ectonucleotidase (AOPCP), suggesting it was due to adenosine arising from breakdown of ATP released through Panx-1 channels. Collectively, these data strongly suggest that purinergic signalling mechanisms mediate crosstalk between CB chemoreceptor and glial cells during chemotransduction.

Ecto‐5′‐nucleotidase (CD73) regulates peripheral chemoreceptor activity and cardiorespiratory responses to hypoxia

“…A direct up‐regulation of CD73 activity in the CB in chronic or chronic intermittent hypoxia remains to be confirmed. However, recent studies suggest that ATP and 5‐HT can both augment ATP release from type 2 cells, thereby amplifying the synaptic ATP concentration (Murali & Nurse, ; Murali et al . ).…”

Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

“…It is also possible that hM3Dq is expressed in GFAP + type II cells in the carotid bodies (86,87) and that these cells modulate the activity of type I neurons via bidirectional purinergic signaling (88). Type I neuron depolarization could lead to CNS-mediated chemoreflexes, including hyperventilation, sympathoexcitation and increases in blood pressure (89).…”

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…It has been hypothesized that the connexin family of gap junction channels may also play a role in facilitating electrical coupling (Murali et al . ; Nurse, ; Murali & Nurse, ). VGCC, voltage‐gated calcium channel.…”

“…ATP released from type I cells during hypoxia or hypercapnia leads to a rise in intracellular Ca 2+ ([Ca 2+ ] i ), followed by a delayed, secondary [Ca 2+ ] i increase in proximal type II cells (Murali et al . ; Murali & Nurse, ). A depolarization of type I cells results in sensory output to the petrosal ganglion and on to the carotid sinus nerve, mediating the cardiorespiratory response in the NTS (Housley et al .…”