Abstract
Exploration of purinergic signaling in brainstem homeostatic control processes is challenging the traditional view that the biphasic hypoxic ventilatory response, which comprises a rapid initial increase in breathing followed by a slower secondary depression, reflects the interaction between peripheral chemoreceptor-mediated excitation and central inhibition. While controversial, accumulating evidence supports that in addition to peripheral excitation, interactions between central excitatory and inhibitory purinergic mechanisms shape this key homeostatic reflex. The objective of this review is to present our working model of how purinergic signaling modulates the glutamatergic inspiratory synapse in the preBötzinger Complex (key site of inspiratory rhythm generation) to shape the hypoxic ventilatory response. It is based on the perspective that has emerged from decades of analysis of glutamatergic synapses in the hippocampus, where the actions of extracellular ATP are determined by a complex signaling system, the purinome. The purinome involves not only the actions of ATP and adenosine at P2 and P1 receptors, respectively, but diverse families of enzymes and transporters that collectively determine the rate of ATP degradation, adenosine accumulation and adenosine clearance. We summarize current knowledge of the roles played by these different purinergic elements in the hypoxic ventilatory response, often drawing on examples from other brain regions, and look ahead to many unanswered questions and remaining challenges.
Highlights
The mammalian brain depends on a constant supply of oxygen (O2) to meet its energy needs, and a host of adaptive responses have evolved to protect brain O2 levels
The biphasic hypoxic ventilatory response has been viewed for decades as the result of just two interacting processes; an initial peripheral, carotid body-mediated (Phase 1) excitation and a slower, centrally mediated hypoxic respiratory depression to a steady-state (Phase 2) level of breathing (Mortola, 1996; Moss, 2000)
Contrary to the long-held view that the biphasic hypoxic ventilatory response is due to two competing processes, we propose at least three processes, a peripheral carotid body mediated excitation that underlies Phase 1, as well as central excitatory and inhibitory processes that interact to determine the time course and magnitude of the secondary depression; we propose a key role for glia in this central excitation
Summary
The mammalian brain depends on a constant supply of oxygen (O2) to meet its energy needs, and a host of adaptive responses have evolved to protect brain O2 levels. While the Phase 1 component of the hypoxic ventilatory response is mediated peripherally, our data from rodents strongly suggest that during hypoxia, astrocytes in the preBötzinger Complex (preBötC, critical site for generating breathing rhythm) detect hypoxia and release ATP, which, via P2Y1 receptors, excites inspiratory neurons and increases ventilation, thereby attenuating the hypoxic respiratory depression (Gourine et al, 2005; Angelova et al, 2015; Rajani et al, 2017; Sheikhbahaei et al, 2018). Efforts to understand purinergic signaling in the hypoxic ventilatory response have largely focused on the inhibitory actions of ADO at P1 receptors, primarily because ADO is so strongly implicated in the profound hypoxic depression in apnea of prematurity (Martin and Abu-Shaweesh, 2005; Funk, 2013; Poalillo and Picone, 2013; Burnstock and Dale, 2015). Lower affinity A2B and A3 receptors may be activated during hypoxia/ischemia/brain injury when ADOe concentrations increase pathologically (Latini and Pedata, 2001; Pedata et al, 2001)
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