Serotonin receptor 1A-modulated phosphorylation of glycine receptor α3 controls breathing in mice.
Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyRα3. The 5-HTR1A-GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
Manzke
Till
T
Department of Neuro- and Sensory Physiology, University of Göttingen, Göttingen, Germany.
Niebert
Marcus
M
Koch
Uwe R
UR
Caley
Alex
A
Vogelgesang
Steffen
S
Hülsmann
Swen
S
Ponimaskin
Evgeni
E
Müller
Ulrike
U
Smart
Trevor G
TG
Harvey
Robert J
RJ
Richter
Diethelm W
DW
D000818:Animals; D002460:Cell Line; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010507:Periodicity; D010766:Phosphorylation; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012119:Respiration; D012701:Serotonin / Q000378:metabolism
D018009:Receptors, Glycine; D011993:Recombinant Fusion Proteins; C113965:glycine receptor alpha3 subunit; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin