Tyrosine kinases enhance the function of glycine receptors in rat hippocampal neurons and human alpha(1)beta glycine receptors.

Full Abstract

Glycine receptors (GlyRs) are transmitter-gated channels that mediate fast inhibitory neurotransmission in the spinal cord and brain. The GlyR beta 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 beta subunit was examined using site-directed mutagenesis and expression of recombinant (alpha(1)beta(Y413F)) receptors in human embryonic kidney (HEK 293) cells. Lavendustin A, an inhibitor of PTKs, depressed glycine-evoked currents (I(Gly)) in CA1 neurons and spinal neurons by 31 % and 40 %, respectively. In contrast, the intracellular application of the exogenous tyrosine kinase, cSrc, enhanced I(Gly) in CA1 neurons by 56 %. cSrc also accelerated GlyR desensitization and increased the potency of glycine 2-fold (control EC(50) = 143 microM; cSrc EC(50) = 74 microM). Exogenous cSrc, applied intracellularly, upregulated heteromeric alpha(1)beta receptors but not homomeric alpha(1) receptors. Substitution mutation of the tyrosine to phenylalanine at position beta-413 prevented this enhancement. Furthermore, a selective inhibitor of the Src family kinases, PP2, down-regulated wild-type alpha(1)beta but not alpha(1)beta(Y413F) receptors. Together, these findings indicate that GlyR function is upregulated by PTKs and this modulation is dependent on the tyrosine-413 residue of the beta subunit.

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Author information

Author/s: Caraiscos, Valerie B (VB); Mihic, S John (SJ); MacDonald, John F (JF); Orser, Beverley A (BA);

Affiliation: Department of Physiology, University of Toronto, Canada.

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of physiology (J Physiol), published in England. (Language: eng)

Reference: 2002-Mar; vol 539 (issue Pt 2) : pp 495-502

Dates: Created 2002/03/07; Completed 2002/06/04; Revised 2008/11/20;

PMID: 11882681, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Down-Regulation - drug effects
Electrophysiology
Enzyme Inhibitors - pharmacology
Hippocampus - cytology; enzymology; metabolism
Humans
Kinetics
Male
Neurons - enzymology; metabolism
Patch-Clamp Techniques

Patch-Clamp Techniques
Phosphorylation
Protein-Tyrosine Kinases - antagonists & inhibitors; metabolism
Rats
Receptors, Glycine - biosynthesis; genetics; metabolism; physiology
Recombinant Proteins - metabolism
Spinal Cord - physiology
Synaptic Transmission - physiology
Tyrosine - physiology
Up-Regulation - drug effects

Associated Chemicals: Enzyme Inhibitors (0) ; Receptors, Glycine (0) ; Recombinant Proteins (0) ; Tyrosine (55520-40-6) ; Protein-Tyrosine Kinases (EC 2.7.1.112)

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