β1-Adrenergic Receptor Association with the Synaptic Scaffolding Protein Membrane-associated Guanylate Kinase Inverted-2 (MAGI-2). Differential regulation of receptor internalization by MAGI-2 AND PSD-95

Jianguo Xu, Maryse Paquet, Anthony G. Lau, Jonathan D. Wood, Christopher A. Ross, Randy A. Hall

Research output: Contribution to journalArticlepeer-review

Abstract

The β-adrenergic receptor (β1AR) is known to be localized to synapses and to modulate synaptic plasticity in many brain regions, but the molecular mechanisms determining β1AR subcellular localization are not fully understood. Using overlay and pull-down techniques, we found that the β1AR carboxyl terminus associates with MAGI-2 (membrane-associated guanylate kinase inverted-2), a protein also known as S-SCAM (synaptic scaffolding molecule). MAGI-2 is a multidomain scaffolding protein that contains nine potential protein-protein interaction modules, including 6 PDZ domains, 2 WW domains, and a guanylate kinase-like domain. The β1AR carboxyl terminus binds with high affinity to the first PDZ domain of MAGI-2, with the last few amino acids of the β1AR carboxyl terminus being the key determinants of the interaction. In cells, the association of full-length β1AR with MAGI-2 occurs constitutively and is enhanced by agonist stimulation of the receptor, as assessed by both co-immunoprecipitation experiments and immunofluorescence co-localization studies. Agonist-induced internalization of the β 1AR is markedly increased by co-expression with MAGI-2. Strikingly, this result is the opposite of the effect of co-expression with PSD-95, a previously reported binding partner of the β1AR. Further cellular experiments revealed that MAGI-2 has no effect on β1AR oligomerization but does promote association of β1AR with the cytoplasmic signaling protein β-catenin, a known MAGI-2 binding partner. These data reveal that MAGI-2 is a specific β1AR binding partner that modulates β1AR function and facilitates the physical association of the β1AR with intracellular proteins involved in signal transduction and synaptic regulation.

Original languageEnglish (US)
Pages (from-to)41310-41317
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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