Integrins Modulate Fast Excitatory Transmission at Hippocampal Synapses

Enikö A Kramár,Joie A Bernard,Christine M Gall,Gary Lynch

doi:10.1074/jbc.m210225200

Abstract

The present study provides the first evidence that adhesion receptors belonging to the integrin family modulate excitatory transmission in the adult rat brain. Infusion of an integrin ligand (the peptide GRGDSP) into rat hippocampal slices reversibly increased the slope and amplitude of excitatory postsynaptic potentials. This effect was not accompanied by changes in paired pulse facilitation, a test for perturbations to transmitter release, or affected by suppression of inhibitory responses, suggesting by exclusion that alterations to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptors cause the enhanced responses. A mixture of function-blocking antibodies to integrin subunits alpha(3), alpha(5), and alpha(v) blocked ligand effects on synaptic responses. The ligand-induced increases were (i) blocked by inhibitors of Src tyrosine kinase, antagonists of N-methyl-d-aspartate receptors, and inhibitors of calcium calmodulin-dependent protein kinase II and (ii) accompanied by phosphorylation of both the Thr(286) site on calmodulin-dependent protein kinase II and the Ser(831) site on the GluR1 subunit of the AMPA receptor. N-Methyl-d-aspartate receptor antagonists blocked the latter two phosphorylation events, but Src kinase inhibitors did not. These results point to the conclusion that synaptic integrins regulate glutamatergic transmission and suggest that they do this by activating two signaling pathways directed at AMPA receptors.

Highlights

Integrins are heterodimeric (␣, ␤), membrane-spanning proteins that anchor cells to the extracellular matrix and to adhesion proteins on opposing cells [1, 2]
Biochemical Results—Pharmacological results presented above are consistent with the hypothesis that RGD-induced increases in fEPSPs are dependent upon activation of calmodulin protein kinase II (CaMKII) followed by phosphorylation of sites on the amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor known to regulate receptor kinetics [51, 52]
The above results provide the first evidence that integrins can influence the size of fast, excitatory synaptic responses in the mature brain

Summary

Introduction

Integrins are heterodimeric (␣, ␤), membrane-spanning proteins that anchor cells to the extracellular matrix and to adhesion proteins on opposing cells [1, 2]. As might be expected from these latter roles, integrins have potent interactions with neighboring membrane-associated proteins, including ion channels [7,8,9,10] and trophic factor receptors [11,12,13,14,15]. Whether these lateral interactions occur in synaptic junctions in the adult brain, which are known to have high concentrations of integrins (16 – 20), has not been studied. The results indicate that integrin binding can increase fast, excitatory synaptic responses and, in addition, provide evidence that they do so by modifying the properties of AMPA-type glutamate receptors

Methods

Results

Conclusion