Binding of amyloid β peptide to β2 adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity

Dayong Wang, G. Govindaiah, Ruijie Liu, Vania De Arcangelis, Charles L. Cox, Yang Kevin Xiang

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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 β2 adrenergic receptor (β2AR). We found that the soluble Aβ binds to β2AR, and the extracellular N terminus of β2AR 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 β2AR, and AMPA receptor-mediated excitatory postsynaptic currents (EPSCs). β2AR 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 β2AR are required for the β2AR/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 nonneurotransmitter Aβ has a binding capacity to β2AR and induces PKA-dependent hyperactivity in AMPA receptors.

Original languageEnglish (US)
Pages (from-to)3511-3521
Number of pages11
JournalFASEB Journal
Volume24
Issue number9
DOIs
StatePublished - Sep 2010
Externally publishedYes

Keywords

  • Alzheimer's disease
  • cAMP
  • EPSC
  • FRET
  • GluR1

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Fingerprint Dive into the research topics of 'Binding of amyloid β peptide to β<sub>2</sub> adrenergic receptor induces PKA-dependent AMPA receptor hyperactivity'. Together they form a unique fingerprint.

  • Cite this