title: Modulation of phrenic motoneuron excitability by ATP: consequences for respiratory-related output in vitro.
abstract: On the basis of the high level of P2X receptor expression found in phrenic motoneurons (MN) in rats (Kanjhan et al., J Comp Neurol 407: 11-32, 1999) and potentiation of hypoglossal MN inspiratory activity by ATP (Funk et al., J Neurosci 17: 6325-6337, 1997), we tested the hypothesis that ATP receptor activation also modulates phrenic MN activity. This question was examined in rhythmically active brain stem-spinal cord preparations from neonatal rats by monitoring effects of ATP on the activity of spinal C4 nerve roots and phrenic MNs. ATP produced a rapid-onset, dose-dependent, suramin- and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid 4-sodium-sensitive increase in C4 root tonic discharge and a 22 +/- 7% potentiation of inspiratory burst amplitude. This was followed by a slower, 10 +/- 5% reduction in burst amplitude. ATPgammaS, the hydrolysis-resistant analog, evoked only the excitatory response. ATP induced inward currents (57 +/- 39 pA) and increased repetitive firing of phrenic MNs. These data, combined with persistence of ATP currents in TTX and immunolabeling for P2X2 receptors in Fluoro-Gold-labeled C4 MNs, implicate postsynaptic P2 receptors in the excitation. Inspiratory synaptic currents, however, were inhibited by ATP. This inhibition differed from that seen in root recordings; it did not follow an excitation, had a faster onset, and was induced by ATPgammaS. Thus ATP inhibited activity through at least two mechanisms: 1) a rapid P2 receptor-mediated inhibition and 2) a delayed P1 receptor-mediated inhibition associated with hydrolysis of ATP to adenosine. The complex effects of ATP on phrenic MNs highlight the importance of ATP as a modulator of central motor outflows.
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors.forename: Gareth B
authors.initials: GB
authors.lastname: Miles
authors.forename: Marjorie A
authors.initials: MA
authors.lastname: Parkis
authors.forename: Janusz
authors.initials: J
authors.lastname: Lipski
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Funk
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009333:Neck; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010507:Periodicity; D010791:Phrenic Nerve / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058476:Receptors, Purinergic P2X2; D012119:Respiration; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology; D013126:Spinal Nerve Roots / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology
chemical_list: D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C022571:adenosine 5'-O-(3-thiotriphosphate); D011732:Pyridoxal Phosphate; D013498:Suramin; D000255:Adenosine Triphosphate