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Tyrosine kinases enhance the function of glycine receptors in rat hippocampal neurons and human α1β glycine receptors

By Valerie B Caraiscos, S John Mihic, John F MacDonald and Beverley A Orser


Glycine receptors (GlyRs) are transmitter-gated channels that mediate fast inhibitory neurotransmission in the spinal cord and brain. The GlyR β subunit contains a putative tyrosine phosphorylation site whose functional role has not been determined. To examine if protein tyrosine kinases (PTKs) regulate the function of GlyRs, we analysed whole-cell currents activated by applications of glycine to CA1 hippocampal neurons and spinal neurons. The role of a putative site for tyrosine phosphorylation at position 413 of the β subunit was examined using site-directed mutagenesis and expression of recombinant (α1βY413F) receptors in human embryonic kidney (HEK 293) cells. Lavendustin A, an inhibitor of PTKs, depressed glycine-evoked currents (IGly) in CA1 neurons and spinal neurons by 31 % and 40 %, respectively. In contrast, the intracellular application of the exogenous tyrosine kinase, cSrc, enhanced IGly in CA1 neurons by 56 %. cSrc also accelerated GlyR desensitization and increased the potency of glycine 2-fold (control EC50 = 143 μm; cSrc EC50 = 74 μm). Exogenous cSrc, applied intracellularly, upregulated heteromeric α1β receptors but not homomeric α1 receptors. Substitution mutation of the tyrosine to phenylalanine at position β-413 prevented this enhancement. Furthermore, a selective inhibitor of the Src family kinases, PP2, down-regulated wild-type α1β but not α1βY413F receptors. Together, these findings indicate that GlyR function is upregulated by PTKs and this modulation is dependent on the tyrosine-413 residue of the β subunit

Topics: Rapid Report
Publisher: Blackwell Science Inc
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Provided by: PubMed Central
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