Modulation of synaptic and channel activities in the respiratory network of the mice by NO/cGMP signalling pathways.
We examined signalling pathways which can involve NO as a second messenger in the respiratory network. In the functional slice preparation, NO donors depressed the respiratory motor output and enhanced its depression after brief episodes of hypoxia. In the inspiratory neurons, NO donors suppressed spontaneous excitatory and inhibitory synaptic currents, activated single K(ATP) channels and inhibited L-type Ca2+ channels. NO scavengers, PTIO and hemoglobin, and the blocker of NO synthase, N-monomethyl-L-arginine, induced effects opposite to those of NO donors and indicated the role of endogenously generated NO in the modulation of the respiratory activity. Using fluorescent dyes DAF-2 and DCF, we imaged NO and reactive oxygen species (ROS). Concentrations of NO and ROS increased during brief episodes of hypoxia and they both contributed to the activation of K(ATP) channels due to oxygen withdrawal. The oxidizing agent t-butyl-hydroperoxide acted similarly to NO donors but it did not interfere with the effects of NO. Increase in cGMP levels with 8-Br-cGMP reproduced the actions of NO donors and occluded the effects of their subsequent applications. We propose that in the respiratory neurons, a constitutive production of NO is responsible for a tonic activation of cGMP-coupled signalling pathways and changes in NO levels modulate the respiratory motor output by altering the activity of K(ATP) and L-type Ca2+ channels.
Mironov
Sergej L
SL
DFG-Center of Molecular Physiology of the Brain, Department of Neuro- and Sensory Physiology, Georg-August-University, Göttingen, Humboldtallee 23, 37073, Germany. smirono@gwdg.de
Langohr
Kersten
K
D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004594:Electrophysiology; D066298:In Vitro Techniques; D051379:Mice; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D012125:Respiratory Center / Q000166:cytology / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D009569:Nitric Oxide; D006152:Cyclic GMP