Rxivist logo

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

By Sharifun Islam, Xiumin Chen, Argel Estrada-Mondragón, Joseph. W. Lynch

Posted 03 Oct 2018
bioRxiv DOI: 10.1101/434357

The a2 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 a2 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 a2 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 a2 GlyRs are functionally modulated. To address this, we investigated whether the a2 GlyR is modulated by phosphorylation at a serine residue (S341) within the same PKA consensus sequence (R-E-S-R) that houses the a3 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 a2 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 a2-mediated glycinergic inhibitory postsynaptic currents. These results suggest that PKA phosphorylation alters the structural and functional properties of the a2 GlyR. This information may help to identify new mechanisms by which a2 GlyRs may be pathologically modified or therapeutically targeted for the treatment of neurological disorders.

Download data

  • Downloaded 395 times
  • Download rankings, all-time:
    • Site-wide: 96,923
    • In neuroscience: 14,372
  • Year to date:
    • Site-wide: 53,710
  • Since beginning of last month:
    • Site-wide: 94,872

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News