Impaired Focal Adhesion Kinase-Grb2 Interaction during Elevated Activity in Hippocampal Neurons

• Main Author: Sachiko Murase
• Format: Article
• Language: English
• Published: MDPI AG 2015-07-01
• Series: International Journal of Molecular Sciences
• Subjects: focal adhesion kinase (FAK); Grb2; Erk1/2; signal transducer and activator of transcription 3 (STAT3); integrin β1; matrix-metalloproteinase (MMP); excitatory/inhibitory (E/I) balance; survival signaling
• Online Access: http://www.mdpi.com/1422-0067/16/7/15659

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.