β3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons.
The integrins are transmembrane receptors for ECM proteins, and they regulate various cellular functions in the central nervous system. In hippocampal neurons, the β3 integrin subtype is required for homeostatic synaptic scaling of AMPA receptors (AMPARs) induced by chronic activity deprivation. The surface level of β3 integrin in postsynaptic neurons directly correlates with synaptic strength and the abundance of synaptic GluA2 AMPAR subunit. Although these observations suggest a functional link between β3 integrin and AMPAR, little is known about the mechanistic basis for the connection. Here we investigate the nature of β3 integrin and AMPAR interaction underlying the β3 integrin-dependent control of synaptic AMPAR expression and thus synaptic strength. We show that β3 integrin and GluA2 subunit form a complex in mouse brain that involves the direct binding between their cytoplasmic domains. In contrast, β3 integrin associates with GluA1 AMPAR subunit only weakly, and, in a heterologous expression system, the interaction requires the coexpression of GluA2. Surprisingly, in hippocampal pyramidal neurons, expressing β3 integrin mutants with either increased or decreased affinity for extracellular ligands has no differential effects in elevating excitatory synaptic currents and surface GluA2 levels compared with WT β3 integrin. Our findings identify an integrin family member, β3, as a direct interactor of an AMPAR subunit and provide molecular insights into how this cell-adhesion protein regulates the composition of cell-surface AMPARs.
Medical Research Council Laboratory for Molecular Cell Biology and Cell Biology Unit,  University College London, London WC1E 6BT,  United Kingdom.
Karine
K
Pozo
Lorenzo A
LA
Cingolani
Silvia
S
Bassani
Fanny
F
Laurent
Maria
M
Passafaro
Yukiko
Y
Goda
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D047468:Immunoprecipitation; D039661:Integrin beta3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D039661:Integrin beta3; D046912:Multiprotein Complexes; D018091:Receptors, AMPA; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C104722:glutamate receptor ionotropic, AMPA 2