The Purinome and the preBötzinger Complex – A Ménage of Unexplored Mechanisms That May Modulate/Shape the Hypoxic Ventilatory Response

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.

ATP signaling in the integrative neural center of Aplysia californica

“…The P2X receptor is one of many different receptors in the purinergic signaling complex. The ‘purinome’ includes P2 receptors, both ionotropic (P2X) and metabotropic (P2Y), P1 adenosine receptors, adenosine transporters ectonucleotidases 49 , 50 . Of note, the Aplysia genome has no P2Y receptors 51 .…”

Geoff Burnstock, purinergic signalling, and chemosensory control of breathing

“…Follow up studies using in vivo animal models provided further evidence that ATP released by brainstem astrocytes contributes to the development of the ventilatory responses to CO2 and hypoxia (Huckstepp et al, 2010b;Gourine et al, 2010;Angelova et al, 2015;Sheikhbahaei et al, 2018b;van de Wiel et al, 2020). An important role played by astrocytes and purinergic signalling in mediating the effects of chemosensory stimuli on the activities of the brainstem cardiovascular and respiratory control networks is supported by the results of experimental studies conducted by other research groups (Lorier et al, 2007;Lorier et al, 2008;Huxtable et al, 2009;Huxtable et al, 2010;Wenker et al, 2010;Zwicker et al, 2011;Wenker et al, 2012;Funk, 2013;Sobrinho et al, 2014;Barna et al, 2016;Rajani et al, 2016;Cinelli et al, 2017;Sobrinho et al, 2017;Hawkins et al, 2017;Rajani et al, 2018;Reklow et al, 2019;Patterson et al, 2021). The notion that ATP release by astrocytes contributes to the hypoxic ventilatory response centrally was met with some scepticism and the readers are invited to evaluate the arguments in favour and against this hypothesis presented in a series of opinion articles (Gourine and Funk, 2017;Funk andGourine, 2018a, 2018b;Teppema, 2018).…”

The role of the adenosine system in epilepsy and its comorbidities

“…Emerging evidence proposes a key mechanistic role for adenosine and adenosine receptors in SUDEP. Significant release of adenosine during seizure activity has the capacity to not only mitigate excessive excitatory activity, but also deleteriously suppress vital central respiratory function in key brain regions, including the brainstem and amygdala (Purnell et al, 2021); primarily via the A 1 and A 2A receptor (Barraco et al, 1990; Phillis et al, 1997; Reklow et al, 2019). In addition to centrally mediated mechanisms, adenosine receptors, particularly the A 2A and A 2B receptor, are expressed in the carotid body, and play a role in modulating the ventilation response, which has been proposed to be involved in SUDEP (Biggs et al, 2022; Conde et al, 2017).…”

“…Moreover, the anti‐somnogenic effects of caffeine limit its utility during the evening hours in which SUDEP occurs. Additionally, the relative roles of A 1 and A 2A receptors in mediating cardiorespiratory depression in the brainstem in SUDEP have not been fully delineated, although a protective effect of A 2A receptor, but not A 1 receptor, antagonism was identified in a SUDEP mouse model (Faingold et al, 2016; Reklow et al, 2019). Based on these insights, it is tempting to speculate whether an A 2A receptor antagonist could provide dual protection against seizure‐induced excitotoxicity and prevention of central respiratory depression.…”