Integrin Signaling Cascades Are Operational in Adult Hippocampal Synapses and Modulate NMDA Receptor Physiology

J Neurochem. 2005 May;93(4):834-49. doi: 10.1111/j.1471-4159.2005.03062.x.

Abstract

Integrin class adhesion proteins are concentrated at adult brain synapses. Whether synaptic integrins engage kinase signaling cascades has not been determined, but is a question of importance to ideas about integrin involvement in functional synaptic plasticity. Accordingly, synaptoneurosomes from adult rat brain were used to test if matrix ligands activate integrin-associated tyrosine kinases, and if integrin signaling targets include NMDA-class glutamate neurotransmitter receptors. The integrin ligand peptide Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) induced rapid (within 5 min) and robust increases in tyrosine phosphorylation of focal adhesion kinase, proline-rich tyrosine kinase 2 and Src family kinases. Increases were similarly induced by the native ligand fibronectin, blocked with neutralizing antibodies to beta1 integrin, and not obtained with control peptides, indicating that kinase activation was integrin-mediated. Both GRGDSP and fibronectin caused rapid Src kinase-dependent increases in tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B in synaptoneurosomes and acute hippocampal slices. Tests of the physiological significance of the latter result showed that ligand treatment caused a rapid and beta1 integrin-dependent increase in NMDA receptor-mediated synaptic responses. These results provide the first evidence that, in adult brain, synaptic integrins activate local kinase cascades with potent effects on the operation of nearby neurotransmitter receptors implicated in synaptic plasticity.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Animals, Newborn
  • Blotting, Western / methods
  • Drug Interactions
  • Electric Stimulation / methods
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / radiation effects
  • Fibronectins / metabolism
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • Hippocampus / cytology*
  • In Vitro Techniques
  • Integrins / classification
  • Integrins / metabolism*
  • Male
  • Microscopy, Electron, Transmission / methods
  • Neurons / drug effects
  • Neurons / physiology*
  • Oligopeptides / pharmacology
  • Oligoribonucleotides, Antisense / pharmacology
  • Patch-Clamp Techniques / methods
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synaptosomes / ultrastructure
  • Time Factors
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • src-Family Kinases / metabolism

Substances

  • AG 1879
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Fibronectins
  • Integrins
  • Oligopeptides
  • Oligoribonucleotides, Antisense
  • Pyrimidines
  • Receptors, N-Methyl-D-Aspartate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • 2-amino-5-phosphopentanoic acid
  • glycyl-arginyl-glycyl-aspartyl-seryl-proline
  • Protein-Tyrosine Kinases
  • Focal Adhesion Kinase 1
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • Ptk2 protein, rat
  • Ptk2b protein, rat
  • src-Family Kinases
  • Valine