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Review
. 2022 Mar 23:15:848642.
doi: 10.3389/fnmol.2022.848642. eCollection 2022.

Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain

Victoria P San Martín  1   2 , Anggelo Sazo  1   2 , Elías Utreras  2   3 , Gustavo Moraga-Cid  1   2 , Gonzalo E Yévenes  1   2
Affiliations
Review

Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain

Victoria P San Martín et al. Front Mol Neurosci. .

Abstract

Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.

Keywords: chronic pain; glycine receptor (GlyR); nociception; phosphorylation; synaptic plasticity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Signaling pathways and molecular mechanisms involved on processes of glycinergic disinhibition in chronic pain. (A) Phosphorylation of dorsal horn GlyRs containing the α1ins subunit. The activation of mGluR5 triggers the ERK-dependent phosphorylation of synaptic α1ins GlyRs. On the other hand, activation of the A1Rs promotes its PP1-mediated de-phosphorylation. Activation of mGluR5 signaling with DHPG decreases the amplitude of Gly-IPSCs, whereas GABA-IPSCs were not affected. (B) IL-1β potentiation of glycinergic synapses. The IL-1β mediated activation of IL1-R generates a long-term potentiation of the Gly-IPSCs on dorsal horn GABAergic neurons. The glycinergic potentiation involves increases on intracellular Ca2+ and p38-MAPK activity. The IL-1β signaling did not affect the GABA-IPSCs. Whether this mechanism preferentially target synaptic α1 or α3-containing GlyRs is unknown. (C) Phosphorylation of dorsal horn GlyRs containing the α3 subunit. Activation of EP2-R by PGE2 decreases the Gly-IPSCs on dorsal horn neurons through the PKA-mediated phosphorylation of synaptic α3 GlyRs. The stimulation of EP2-R did not modify the GABA-IPSCs. The molecular identity of potential GPCRs involved in the de-phosphorylation of dorsal horn α3GlyRs remains undetermined. (D) Molecular mechanisms underlying the mGluR5-mediated glycinergic dis-inhibition. Activation of mGluR5 stimulate the binding of ERK to a consensus site located on the splice cassette (380SPMLNLPQ) within the ICD of α1insGlyR. ERK targets and phosphorylate the S380 residue and stimulate the subsequent ubiquitination of the L379 residue through the E3 ubiquitin ligase HUWE, triggering the proteasomal degradation of α1ins GlyRs. (E) Molecular mechanisms underlying the EP2-R mediated glycinergic dis-inhibition. Activation of EP2-Rs triggers the PKA-dependent phosphorylation of S346 of α3GlyRs, leading to alterations on the ion channel function and to enhanced lateral mobility of the receptor.
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References

    1. Acuña M. A., Yévenes G. E., Ralvenius W. T., Benke D., Di Lio A., Lara C. O., et al. (2016). Phosphorylation state–dependent modulation of spinal glycine receptors alleviates inflammatory pain. J. Clin. Invest. 126 2547–2560. 10.1172/JCI83817 - DOI - PMC - PubMed
    1. Ahmadi S., Lippross S., Neuhuber W. L., Zeilhofer H. U. (2002). PGE 2 selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat. Neurosci. 5 34–40. 10.1038/nn778 - DOI - PubMed
    1. Avila A., Vidal P. M., Dear T. N., Harvey R. J., Rigo J. M., Nguyen L. (2013). Glycine receptor α2 subunit activation promotes cortical interneuron migration. Cell rep. 4 738–750. 10.1016/j.celrep.2013.07.016 - DOI - PMC - PubMed
    1. Bai H. H., Liu J. P., Yang L., Zhao J. Y., Suo Z. W., Yang X., et al. (2017). Adenosine A1 receptor potentiated glycinergic transmission in spinal cord dorsal horn of rats after peripheral inflammation. Neuropharmacology 126 158–167. 10.1016/j.neuropharm.2017.09.001 - DOI - PubMed
    1. Beyer C., Roberts L. A., Komisaruk B. R. (1985). Hyperalgesia induced by altered glycinergic activity at the spinal cord. Life sci. 37 875–882. 10.1016/0024-3205(85)90523-5 - DOI - PubMed

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