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ATP and central respiratory control: a three-part signaling system Open Access


Other title
PreBotzinger Complex
Type of item
Degree grantor
University of Alberta
Author or creator
Zwicker, Jennifer D
Supervisor and department
Funk, Gregory D (Physiology, University of Alberta)
Examining committee member and department
Cheung, Po-Yin (Pharmacology, University of Alberta)
Wilson, Christopher G (Physiology and Biophysics, Case Western Reserve University )
Posse de Chaves, Elena (Pharmacology, University of Alberta)
Greer, John J (Physiology, University of Alberta)
Ballanyi, Klaus (Physiology, University of Alberta)
Department of Physiology

Date accepted
Graduation date
Doctor of Philosophy
Degree level
ATP actions on central inspiratory networks are determined by a three-part signaling system comprising: i) excitatory actions of ATP at P2 receptors (Rs) ii) ectonucleotidases that degrade ATP into adenosine (ADO), and iii) inhibitory actions of ADO at P1Rs. During hypoxia, an initial increase in ventilation is followed by a secondary depression that is life threatening in premature infants. The release of ATP in respiratory networks, including the preBötzinger Complex (preBötC, inspiratory rhythm generation site) attenuates this secondary ventilatory depression. However, subsequent degradation of ATP to ADO may exacerbate the depression. The objective of my thesis research is to explore the significance of this three-part signaling system for preBötC networks in rodents using rhythmically active medullary slices from rats and mice, primary cultures of preBötC glia, and anesthetized adult rats. In neonatal rats in vitro, injection of ATP into the preBötC evokes an increase in inspiratory breathing frequency via a P2Y1R mechanism that involves both neurons and glia. Analysis of cultured preBötC glia suggests that P2Y1R stimulation evokes an increase in Ca2+ and release of glutamate, which excites inspiratory neurons. In contrast, injection of ATP into the preBötC of rhythmic slices from neonatal mice evokes a P2Y1R-mediated frequency increase if A1 ADORs are blocked. In contrast to rats, neonatal mice are sensitive to ADO inhibition of preBötC frequency and have higher expression of the ectonucleotidase TNAP (an enzyme that degrades ATP to ADO). A delicate balance between P2R actions and P1R actions modulates the preBötC network of neonatal rodents. Purinergic signaling also influences the activity of mature preBötC networks in adult rats. Injection of a P2Y1R agonist into the preBötC evoked a 40% increase in respiratory frequency while ADO injection had no effect. As predicted based on the proposed role of ATP in attenuating the secondary hypoxic ventilatory depression, the increase of endogenous ectonucleotidase activity in the preBötC (via injection of a lentivirus controlling expression of the enzyme TMPAP) produced a greater secondary hypoxic ventilatory depression compared to control. This work lays the foundation for future research examining the importance of glia and purinergic modulation within the rhythmogenic inspiratory network.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Huxtable AG*, Zwicker JD*, Alvares TS, Ruangkittisakul, A, Fang X, Hahn LB, Posse de Chaves E, Baker GB, Ballanyi K, Funk GD. (2010) Glia contribute to the purinergic modulation of inspiratory rhythm generating networks. J Neurosci, 30(11):3947-3958 *AGH and JDZ contributed equally to this workZwicker JD, Rajani V, Hahn LB, Funk GD Purinergic modulation of preBötzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine. J Physiol 2011. 589:4583-4600.

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