Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Abstract

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-HTR 1A -specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR 1A and GlyRα3. The 5-HTR 1A -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-HTR 1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR 1A -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.

Control of Ethanol Sensitivity of the Glycine Receptor α3 Subunit by Transmembrane 2, the Intracellular Splice Cassette and C-Terminal Domain

“…They are also found in Botzinger complex, Pre-Botzinger complex, and spinal trigeminal nucleus in the brainstem where they appear to control rhythmic activity of respiratory networks (Manzke et al, 2010). Overall, our data support the conclusion that GlyRs containing a3 in these locations are relatively insensitive to ethanol and Gbg modulation.…”

“…Furthermore, it is also unknown whether this GlyR subtype is modulated by Gbg. This subunit has clinical significance because it is involved in the control of rhythmic breathing (Manzke et al, 2010), and ethanol modulation of this GlyR subtype could be responsible for the respiratory depression induced by excessive alcohol consumption. In addition, modulation of a3 GlyRs by Gbg through the activation of G protein-coupled receptors could be relevant for the regulation of glycinergic inhibition in other physiologic processes, such as central pain sensitization (Harvey et al, 2004;Manzke et al, 2010).…”

Mutations in the GlyT2 Gene (SLC6A5) Are a Second Major Cause of Startle Disease

“…Another potential explanation for these differences is that defective presynaptic glycine uptake is predicted to affect the function of multiple GlyR subtypes, i.e., ␣2␤ and ␣3␤, as well as the predominant ␣1␤ isoform. In this regard, it is noteworthy that GlyR ␣3 knock-out mice were recently shown to have an irregular respiratory rhythm (45).…”

A latent serotonin-1A receptor-gated spinal afferent pathway inhibiting breathing

“…Previous studies have shown that systemic 5-HT 1A R agonists can reverse the apneustic disturbances (i.e., pronounced prolongation of inspiratory duration) resulting from a variety of respiratory defects in patients and animal models (Wilken et al 1997), presumably via 5-HT 1A R-mediated enhancement of glycinergic inhibition in brainstem respiratory networks (Manzke et al 2009(Manzke et al , 2010. Consistent with this view, we found that microinjection of the specific NMDA (NMethyl-D-aspartate) receptor antagonist AP5 (20 mM) into the KFN unilaterally induced an apneustic pattern ( Fig.…”