Autocrine and paracrine actions of ATP in rat carotid body

Abstract

Carotid bodies are peripheral chemoreceptors that detect lowering of arterial blood O(2) level. The carotid body comprises clusters of glomus (type I) cells surrounded by glial-like sustentacular (type II) cells. Hypoxia triggers depolarization and cytosolic [Ca(2+)] ([Ca(2+)](i)) elevation in glomus cells, resulting in the release of multiple transmitters, including ATP. While ATP has been shown to be an important excitatory transmitter in the stimulation of carotid sinus nerve, there is considerable evidence that ATP exerts autocrine and paracrine actions in carotid body. ATP acting via P2Y(1) receptors, causes hyperpolarization in glomus cells and inhibits the hypoxia-mediated [Ca(2+)](i) rise. In contrast, adenosine (an ATP metabolite) triggers depolarization and [Ca(2+)](i) rise in glomus cells via A(2A) receptors. We suggest that during prolonged hypoxia, the negative and positive feedback actions of ATP and adenosine may result in an oscillatory Ca(2+) signal in glomus cells. Such mechanisms may allow cyclic release of transmitters from glomus cells during prolonged hypoxia without causing cellular damage from a persistent [Ca(2+)](i) rise. ATP also stimulates intracellular Ca(2+) release in sustentacular cells via P2Y(2) receptors. The autocine and paracrine actions of ATP suggest that ATP has important roles in coordinating chemosensory transmission in the carotid body.

Carotid chemoreceptor “resetting” revisited

“…In sharp contrast, ATP triggers a large, transient [Ca 2+ ] i rise in CB type II cells, reportedly via purinergic P2Y 2 receptors (Xu et al, 2003). Glial cells in other systems are known to amplify synaptic transmission by releasing additional ATP and a similar hypothesis was recently advanced by several authors for the CB, although evidence that type II cells release ATP was lacking (Nurse, 2010; Tse et al, 2012). This model (Fig.…”

“…Donnelly has proposed that persistent Na + currents in CSN nerve endings (9) may enhance nerve terminal excitability and amplify excitation by neurotransmitters, potentially explaining how a 2–3 fold increase in neurotransmitter release during hypoxia can result in a 20–30 fold increase in single unit CSN activity (Donnelly, 2011). Finally, ATP increases [Ca 2+ ] i in type II cells and may result in release of additional ATP as a “gliotransmitter” as well as release of other modulators (Tse et al, 2012; Zhang et al, 2012). This has led to a recent surge of interest in the glia-like type II cells as synaptic amplifiers of chemotransduction, similar to the role of glial cells in other neural tissues (Butt, 2011).…”

Role of K2P channels in stimulus-secretion coupling

“…Such [Ca 2+ ] i oscillations could account for the basal release of catecholamines in normoxia unrelated to any effect on TASK activity. Autocrine actions of transmitters such as ATP and adenosine may also assist in spontaneous fluctuations in Em and [Ca 2+ ] i [59]. Clearly, more definitive studies are needed to understand the relative contributions of TASK and BK to hypoxia-induced depolarization, rise in [Ca 2+ ] i and transmitter secretion in vitro and in vivo .…”

Evidence for protein kinase involvement in the 5‐HT–[Ca2+]i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

“…In fact, intracellular Ca 2+ responses in type II cells could be elicited by nanomolar concentrations of 5-HT, and were surprisingly more frequent and more robust compared with responses in neighbouring type I cells (Murali et al, 2017), which often failed to respond to 5-HT (Gronblad et al, 1983;Liu et al, 2011;Murali et al, 2017;Oomori et al, 1994;Yokoyama et al, 2013;. Stimulation of 5-HT2Rs and other G-protein-coupled receptors, including purinergic P2Y2Rs, on type II cells leads to activation of ATP-permeable channels with properties similar to pannexin-1 (Panx-1) channels (Murali et al, 2017;Murali, Zhang, & Nurse, 2014Tse, Yan, Lee, & Tse, 2012;Xu, Tse, & Tse, 2003;Zhang et al, 2012).…”