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

  • Author / Creator
    Zwicker, Jennifer D
  • 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.

  • Subjects / Keywords
  • Graduation date
    2012-09
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3SH4P
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Physiology
  • Supervisor / co-supervisor and their department(s)
    • Funk, Gregory D (Physiology, University of Alberta)
  • Examining committee members and their departments
    • Wilson, Christopher G (Physiology and Biophysics, Case Western Reserve University )
    • Greer, John J (Physiology, University of Alberta)
    • Ballanyi, Klaus (Physiology, University of Alberta)
    • Cheung, Po-Yin (Pharmacology, University of Alberta)
    • Posse de Chaves, Elena (Pharmacology, University of Alberta)