title: Impaired Focal Adhesion Kinase-Grb2 Interaction during Elevated Activity in Hippocampal Neurons.
abstract: Excitatory/inhibitory imbalances are implicated in many neurological disorders. Previously, we showed that chronically elevated network activity induces vulnerability in neurons due to loss of signal transducer and activator of transcription 3 (STAT3) signaling in response to the impairment of the serine/threonine kinase, extracellular-signal-regulated kinases 1/2 (Erk1/2) activation. However, how phosphorylation of Erk1/2 decreases during elevated neuronal activity was unknown. Here I show the pErk1/2 decrease induced by 4-aminopyridine (4-AP), an A-type potassium channel inhibitor can be blocked by a broad-spectrum matrix-metalloproteinase (MMP) inhibitor, FN-439. Surface expression levels of integrin β1 dramatically decrease when neurons are challenged by chronically elevated activity, which is reversed by FN-439. Treatment with 4-AP induces degradation of focal adhesion kinase (FAK), the mediator of integrin signaling. As a result, interactions between FAK and growth factor receptor-bound protein 2 (Grb2), the adaptor protein that mediates Erk1/2 activation by integrin, are severely impaired. Together, these data suggest the loss of integrin signaling during elevated activity causes vulnerability in neurons.
authors.affiliation: Laboratory of Molecular Biology, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. smurase@umd.edu.|Department of Biology and Neuroscience and Cognitive Sciences Program, University of Maryland, College Park, MD 20742, USA. smurase@umd.edu.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D019012:Integrin beta1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C095170:4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid; D051380:GRB2 Adaptor Protein; D006877:Hydroxamic Acids; D019012:Integrin beta1; D009842:Oligopeptides; D050796:STAT3 Transcription Factor; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Erk1/2; Grb2; excitatory/inhibitory (E/I) balance; focal adhesion kinase (FAK); integrin β1; matrix-metalloproteinase (MMP); signal transducer and activator of transcription 3 (STAT3); survival signaling