Abstract
The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity. In particular, the rapid insertion of the GluA1 homomeric (GluA1-homo) AMPARs into the postsynaptic membrane is considered to be critical in the expression of hippocampal CA1 long-term potentiation (LTP), which is important for certain forms of learning and memory. However, how the formation and trafficking of GluA1-homo AMPARs are regulated remains poorly understood. Here, we report that p97 specifically interacts with and promotes the formation of GluA1-homo AMPARs. The association with p97 retains GluA1-homo AMPARs in the intracellular compartment under basal conditions, and its dissociation allows GluA1-homo AMPARs to be rapidly inserted into the postsynaptic membrane shortly after LTP induction. Thus, our results shed lights into the molecular mechanisms by which p97 regulates GluA1-homo AMPARs formation and trafficking, thereby playing a critical role in mediating synaptic plasticity.
Highlights
The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptors (AMPARs) mediate the fast excitatory synaptic transmission in the mammalian brain and are important for synaptic plasticity
Through its specific interaction with the GluA1 subunit, p97 promotes the formation of GluA1-homo AMPARs and retains them intracellularly
By interacting with GluA1, p97 promotes the formation of GluA1-homo AMPARs at the expense of reducing the GluA1/GluA2 heteromeric AMPARs
Summary
P97 is a GluA1-homo AMPARs interacting protein. In order to investigate AMPARs subunit-specific interacting proteins, we raised polyclonal antibodies against the C-terminal of the GluA1 or GluA2 subunit, the two major subunits of the native AMPARs expressed in the hippocampus. 50 pA 10 ms n.s. If our reasoning is correct, one can expect that overexpression of p97 would increase its ability to retain native GluA1-homo AMPARs in the intracellular compartment, thereby reducing cell surface expression of the receptor under basal conditions or following LTP induction. If our reasoning is correct, one can expect that overexpression of p97 would increase its ability to retain native GluA1-homo AMPARs in the intracellular compartment, thereby reducing cell surface expression of the receptor under basal conditions or following LTP induction We tested this prediction by overexpressing p97 in hippocampal CA1 neurons by injecting AAV9YFP-p2a-p97 or AAV9-GFP as control into the mouse ventricles at P0. NMDAR mediated eEPSCs were not affected by p97 overexpression (Supplementary Fig. 3)
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