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bioRxiv · 10.1101/434357

Phosphorylation of the alpha2 glycine receptor induces an extracellular conformational change and slows the rise and decay rates of glycinergic synaptic currents

Islam, S.·Chen, X.·Estrada-Mondragon, A.·Lynch, J.
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Abstract

The 2 glycine receptor (GlyR) is a pentameric ligand-gated anion channel that plays a key role in cortical interneuron migration and in the differentiation of cortical progenitor cells into functional neurons. It also mediates tonic inhibitory chloride currents in adult forebrain neurons. Disruption of 2 GlyR gene expression or receptor function results in the aberrant functioning of neuronal circuits which contributes to the pathophysiology of schizophrenia, autism and epilepsy. This implicates the 2 GlyR as a possible therapeutic target for a range of neurological disorders. However, despite its therapeutic potential, little is known about the mechanisms by which 2 GlyRs are functionally modulated. To address this, we investigated whether the 2 GlyR is modulated by phosphorylation at a serine residue (S341) within the same PKA consensus sequence (R-E-S-R) that houses the 3 GlyR S346 residue that is known to be phosphorylated by PKA. Resolving this question might uncover a novel means of physiologically, pathologically or therapeutically modulating 2 GlyRs. We show using voltage-clamp fluorometry that forskolin-induced phosphorylation of S341 induces a conformational change in the glycine binding site. We also employed glycinergic artificial synapses to demonstrate that the S341E phospho-mimetic mutation slows the rise and decay rates of 2-mediated glycinergic inhibitory postsynaptic currents. These results suggest that PKA phosphorylation alters the structural and functional properties of the 2 GlyR. This information may help to identify new mechanisms by which 2 GlyRs may be pathologically modified or therapeutically targeted for the treatment of neurological disorders.

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Islam, S., Chen, X., Estrada-Mondragon, A., Lynch, J.. 2018-10-03. Phosphorylation of the alpha2 glycine receptor induces an extracellular conformational change and slows the rise and decay rates of glycinergic synaptic currents. https://doi.org/10.1101/434357

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