ATP in central respiratory control: A three-part signaling system
Introduction
The vital flow of air into and out of the lungs in mammals is generated by the precisely coordinated, rhythmic contraction and relaxation of respiratory pump, airway and accessory muscles that are controlled by an oscillatory neuronal network in the brainstem. The activity in this network is robust and tightly controlled to allow for homeostatic maintenance of ventilation. It is also highly modulated, which is an important factor underlying the striking adaptability of the respiratory control system. The level of motor output and ultimately ventilation are matched to environmental and behavioural demands that vary over 100-fold on multiple time scales (Feldman et al., 2003) relevant to changes in activity, posture, state (sleep–wake), development or disease. The insight into basic mechanisms of signal transduction and how these cascades impact on neural network behaviour, the potential involvement of these modulatory systems in central nervous system disorders of breathing and the prospect of developing pharmacological therapies for these disorders has motivated intense research into the mechanisms underlying neuromodulation of respiratory circuits.
The focus of this review is on the role of ATP and purinergic signaling in central respiratory control. It was first proposed more than 35 years ago that ATP is a transmitter, released with norepinephrine (NE) to mediate nonadrenergic–noncholinergic neurotransmission (NANC) to smooth muscle (Burnstock, 1997, Burnstock, 2006a, Burnstock, 2007). However, it was not until the early 1990s, following the demonstration that ATP contributes to fast (ionotropic) neuron-to-neuron signaling in both peripheral ganglia and the central nervous system (CNS), and the subsequent cloning of P2Y (Webb et al., 1993) and P2X receptors (Brake et al., 1994, Valera et al., 1994), that interest in purinergic signaling began to surge.
Understanding of the molecular biology of P2 receptors and the properties of recombinant receptors has advanced enormously since then, and exceeds the knowledge of the physiological significance of puringergic signaling for brain function, reflecting in part the lack of selective receptor antagonists. However, the gap is narrowing. P2 receptor-mediated, neuron–neuron signaling has been demonstrated in multiple brain regions (Burnstock, 2007). In the respiratory control system, P2 receptor signaling is most strongly implicated in chemosensation and the homeostatic ventilatory responses to hypoxia and hypercapnia (Gourine, 2005). Data are most compelling in the carotid body where ATP and P2 receptor signaling play critical roles in afferent signal transmission as well as in the efferent, inhibitory control of carotid body activity (Campanucci and Nurse, 2007, Lahiri et al., 2007).
Understanding of P2 receptor signaling and its significance for the central neural control of breathing is less complete. However, the field has taken a significant leap forward with the demonstration, using novel ATP sensors, that ATP is released in respiratory and chemosensitive areas of the medulla in response to hypoxia and hypercapnia, and that P2 receptor signaling contributes to the respective homeostatic ventilatory responses (Gourine, 2005, Gourine et al., 2005a, Gourine et al., 2005b).
Our purpose here is to review the role(s) of P2 receptor signaling in central respiratory control and our understanding of underlying mechanism(s). We have approached this discussion from the perspective that ATP signaling is best considered as a three-part system in which the net effect will reflect a dynamic interaction between the signaling actions of ATP and ADP at P2 receptors, the spatiotemporal distribution of ectonucleotidases that differentially metabolize ATP into ADP, AMP and adenosine, and the signaling actions of adenosine at P1 receptors. The dynamics of this interplay are especially relevant for respiratory control because adenosine is implicated as a respiratory depressant in adult (Eldridge et al., 1984, Yamamoto et al., 1994), newborn (Herlenius et al., 1997, Runold et al., 1989) and especially fetal mammals (Bissonnette et al., 1990). It is also implicated in the hypoxia-induced depression of ventilation (Moss, 2000). The review therefore comprises 4 main sections, including: (i) a brief description of the molecular biology of P2 receptors, P1 receptors and ectonucleotidases; (ii) an historical perspective on the role of P2 signaling in central respiratory chemosensitivity; (iii) a review of what is known of how each limb in this three-part signaling system differs between rhythm generating and motoneuron compartments of the central respiratory network, and; (iv) an overview of questions and technical challenges that remain.
Section snippets
P2 receptors
Two major families of P2 receptors mediate the actions of ATP. P2X receptors, comprising 7 receptor subtypes (P2X1–7) and a variety of splice variants, are ligand-gated, ionotropic, trimeric, non-selective cation channels with a significant Ca2+ permeability that mediate fast excitatory responses (Burnstock, 2007). P2Y receptors mediate slower responses to ATP, but also ADP, via G-proteins. There are 8 different P2Y receptors (in humans; P2Y1,2,4,6,11–14) that can divided into two main
CO2 sensitivity
Interest in the role of P2 receptor signaling in central respiratory control and CO2 sensitivity began in the mid 90's and derived from four main observations: (i) intense P2X2 receptor subunit staining in motoneurons and throughout the ventrolateral medulla, including the preBötC (Gourine et al., 2003, Kanjhan et al., 1999, Lorier et al., 2004, Lorier et al., 2007, Thomas et al., 2001, Yao et al., 2000); (ii) dendritic arborizations of VRC and preBötC inspiratory neurons into chemosensitive
The three-part signaling system underlying the actions of ATP: differential dynamics in rhythm generating and motor output compartments of the central respiratory network
This section will summarize current understanding of the mechanisms through which ATP and its metabolites affect the cellular, synaptic and network properties of respiratory related nuclei and neurons. Specifically, we will compare what is known of P2 and P1 receptor signaling and ectonucleotidase activity in ventral medullary rhythm generating circuits and inspiratory motoneuron pools. An important point is that mechanistic data derive primarily through exogenous application of agonists.
Endogenous ATP: conditions of release and sources
Understanding of the physiological significance of ATP signaling for respiratory control at all levels of system organization requires more information regarding the stimuli/conditions that evoke release, and its source(s). In central respiratory regions, endogenous ATP release has only been demonstrated from the ventral medullary surface (Gourine et al., 2005a, Gourine et al., 2005b), the VRC (Gourine et al., 2005b) and the NTS (Spyer and Thomas, 2000) where it contributes to the ventilatory
Acknowledgements
We acknowledge Prof. N Dale and Dr. DK Mulkey for their comments. This work was supported by the Alberta Heritage Foundation for Medical Research (AHFMR), Canadian Institute for Health Research (CIHR), Canadian Foundation for Innovation (CFI), and the Alberta Science and Research Authority (ASRA). GDF is an AHFMR Scientist.
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