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Binding of amyloid β peptide to β 2 adrenergic receptor induces PKA‐dependent AMPA receptor hyperactivity
Author(s) -
Wang Dayong,
Govindaiah G.,
Liu Ruijie,
De Arcangelis Vania,
Cox Charles L.,
Xiang Yang K.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-156661
Subject(s) - ampa receptor , chemistry , receptor , microbiology and biotechnology , postsynaptic potential , glutamate receptor , postsynaptic density , amyloid precursor protein , biology , medicine , biochemistry , alzheimer's disease , disease
Progressive decrease in neuronal function is an established feature of Alzheimer's disease (AD). Previous studies have shown that amyloid β (Aβ) peptide induces acute increase in spontaneous synaptic activity accompanied by neurotoxicity, and Aβ induces excitotoxic neuronal death by increasing calcium influx mediated by hyperactive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptors. An in vivo study has revealed subpopulations of hyperactive neurons near Aβ plaques in mutant amyloid precursor protein (APP)‐transgenic animal model of Alzheimer's disease (AD) that can be normalized by an AMPA receptor antagonist. In the present study, we aim to determine whether soluble Aβ acutely induces hyperactivity of AMPA receptors by a mechanism involving β 2 adrenergic receptor (β 2 AR). We found that the soluble Aβ binds to β 2 AR, and the extracellular N terminus of β 2 AR is critical for the binding. The binding is required to induce G‐protein/cAMP/protein kinase A (PKA) signaling, which controls PKA‐dependent phosphorylation of GluR1 and β 2 AR, and AMPA receptor‐mediated excitatory postsynaptic currents (EPSCs). β 2 AR and GluR1 also form a complex comprising postsynaptic density protein 95 (PSD95), PKA and its anchor AKAP150, and protein phosphotase 2A (PP2A). Both the third intracellular (i3) loop and C terminus of β 2 AR are required for the β 2 AR/AMPA receptor complex. Aβ acutely induces PKA phosphorylation of GluR1 in the complex without affecting the association between two receptors. The present study reveals that non‐neurotransmitter Aβ has a binding capacity to β 2 AR and induces PKA‐dependent hyperactivity in AMPA receptors.—Wang, D., Govindaiah, G., Liu, R., De Arcangelis, V., Cox, C. L., Xiang, Y. K. Binding of amyloid β peptide to β 2 adrenergic receptor induces PKA‐dependent AMPA receptor hyperactivity. FASEB J . 24, 3511–3521 (2010). www.fasebj.org