β3 integrin interacts directly with GluA2 AMPA receptor subunit and regulates AMPA receptor expression in hippocampal neurons

Abstract

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.homeostatic synaptic plasticity | extracellular matrix | excitatory synaptic transmission S ynapses receive, integrate, and transmit information across neural networks, and use-dependent changes in synaptic efficacy are thought to underlie a variety of brain functions from computations to learning and memory. The activity-dependent changes in synaptic properties rely on the coordinated actions of a vast array of molecules in the pre-and the postsynaptic neurons. At excitatory synapses, changes in postsynaptic AMPA receptor (AMPAR) number are crucial for regulating synaptic strength. Insertion and removal of postsynaptic AMPARs contribute directly to some forms of long-term potentiation and long-term depression (1, 2) and to homeostatic synaptic plasticity, which is a compensatory mechanism engaged by neurons in response to chronic changes in network activity (3, 4). Delineating the mechanisms governing the trafficking of AMPARs is a key step toward understanding the basis of functional plasticity at excitatory synapses.Growing evidence indicates that synaptic cell-adhesion molecules are important players in regulating synaptic plasticity. They bridge pre-and postsynaptic membranes and coordinate morphological and functional synaptic changes across the synaptic cleft (5, 6). In this respect, the integrins are of special interest. They are heterodimers consisting of an α-and a β-subunit, and they mediate cell-ECM and cell-cell adhesions (7). Unlike other cell-adhesion molecules, int...

AMPA receptor exchange underlies transient memory destabilization on retrieval

“…Importantly, blocking the synaptic removal of GluA2-containing CI-AMPARs during retrieval prevented this AMPAR composition exchange, and also protected the consolidated memory against becoming labile. Because GluA2 stabilizes dendritic spines (26,28) and retains AMPARs at synapses through direct interaction with synaptic proteins (11,(23)(24)(25)(26)(27), the loss of CI-AMPARs may destabilize potentiated synaptic strength, and hence memory. Our results suggest that other manipulations leading to synaptic removal of CI-AMPARs may destabilize consolidated memory as well.…”

“…Given that GluA2 stabilizes AMPARs at synapses through interaction with synaptic proteins (11,(23)(24)(25)(26)(27) and also stabilizes dendritic spines (26,28), supporting memory storage (29)(30)(31), CI-AMPAR endocytosis may destabilize the potentiated synaptic strength underlying consolidated memory. We tested whether the memory retrievalinduced decrease in CI-AMPARs is critical for rendering the memory unstable using GluA2 3Y .…”

Activity-dependent PI(3,5)P 2 synthesis controls AMPA receptor trafficking during synaptic depression

“…Here, we found that brief PIKfyve inhibition during NMDA stimulation blocks internalization of GluA2 and that PIKfyve inhibition immediately following NMDA stimulation hastens the recovery of surface GluA2 levels after internalization. The GluA2 subunit plays an instructive role in homeostatic plasticity induced by chronic changes in activity (67,69,78,79,83,84), thereby providing a potential link between PI(3,5)P 2 synthesis during sustained activity changes and the regulation of AMPAR expression at the cell surface. Our results are consistent with up-regulation of PI(3,5)P 2 levels driving AMPAR internalization and PI(3,5)P 2 acting by delaying or diverting internalized receptors from recycling back to the plasma membrane.…”

The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression

“…Integrin receptors and ion channels communicate by diffusible signals (16)(17)(18)(19)(20) as well as by forming macromolecular complexes (21)(22)(23)(24)(25). In particular, the b 1 integrin-mediated adhesion to fibronectin activates hERG1 currents (I hERG1 ) in different cell types (17,26).…”