title: Purinergic modulation of preBötzinger complex inspiratory rhythm in rodents: the interaction between ATP and adenosine.
abstract: ATP signalling in the CNS is mediated by a three-part system comprising the actions of ATP (and ADP) at P2 receptors (P2Rs), adenosine (ADO) at P1 receptors (P1Rs), and ectonucleotidases that degrade ATP into ADO. ATP excites preBötzinger complex (preBötC) inspiratory rhythm-generating networks where its release attenuates the hypoxic depression of breathing. Its metabolite, ADO, inhibits breathing through unknown mechanisms that may involve the preBötC. Our objective is to understand the dynamics of this signalling system and its influence on preBötC networks. We show that the preBötC of mouse and rat is sensitive to P2Y(1) purinoceptor (P2Y(1)R) activation, responding with a >2-fold increase in frequency. Remarkably, the mouse preBötC is insensitive to ATP. Only after block of A(1) ADORs is the ATP-evoked, P2Y(1)R-mediated frequency increase observed. This demonstrates that ATP is rapidly degraded to ADO, which activates inhibitory A(1)Rs, counteracting the P2Y(1)R-mediated excitation. ADO sensitivity of mouse preBötC was confirmed by a frequency decrease that was absent in rat. Differential ectonucleotidase activities are likely to contribute to the negligible ATP sensitivity of mouse preBötC. Real-time PCR analysis of ectonucleotidase isoforms in preBötC punches revealed TNAP (degrades ATP to ADO) or ENTPDase2 (favours production of excitatory ADP) as the primary constituent in mouse and rat, respectively. These data further establish the sensitivity of this vital network to P2Y(1)R-mediated excitation, emphasizing that individual components of the three-part signalling system dramatically alter network responses to ATP. Data also suggest therapeutic potential may derive from methods that alter the ATP-ADO balance to favour the excitatory actions of ATP.
authors.affiliation: Departments of Physiology and Pediatrics, Centre for Neuroscience, Women and Children’s Health Research Institute (WCHRI), Faculty of Medicineand Dentistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7.
authors.forename: J D
authors.initials: JD
authors.lastname: Zwicker
authors.forename: V
authors.initials: V
authors.lastname: Rajani
authors.forename: L B
authors.initials: LB
authors.lastname: Hahn
authors.forename: G D
authors.initials: GD
authors.lastname: Funk
mesh_terms: D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D055724:Electrophysiological Phenomena; D000860:Hypoxia / Q000503:physiopathology; D001239:Inhalation / Q000187:drug effects / Q000502:physiology*; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D010507:Periodicity; D017207:Rats, Sprague-Dawley; D058472:Receptors, Purinergic P2Y1 / Q000187:drug effects / Q000502:physiology*; D012125:Respiratory Center / Q000187:drug effects / Q000502:physiology*; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate; D000241:Adenosine