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Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Abstract : Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional reduction in GlyRs containing the a3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKA-dependent phosphorylation of a3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional a3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of a3GlyRs. We show in addition that the substitution of the PKA-targeted serine with a negatively charged residue within the ICD of a3GlyRs and of chimeric receptors combining bacterial GLIC and a3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03088069
Contributor : Pierre-Jean Corringer <>
Submitted on : Friday, December 25, 2020 - 7:42:35 AM
Last modification on : Tuesday, January 5, 2021 - 3:27:52 AM

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Gustavo Moraga-Cid, Victoria San Martín, Cesar Lara, Braulio Muñoz, Ana Marileo, et al.. Modulation of glycine receptor single-channel conductance by intracellular phosphorylation. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.4804. ⟨10.1038/s41598-020-61677-w⟩. ⟨pasteur-03088069⟩

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