1-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*

نویسندگان

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

The 1-adrenergic receptor ( 1AR) is known to be localized to synapses and to modulate synaptic plasticity in many brain regions, but the molecular mechanisms determining 1AR subcellular localization are not fully understood. Using overlay and pull-down techniques, we found that the 1AR 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 1AR carboxyl terminus binds with high affinity to the first PDZ domain of MAGI-2, with the last few amino acids of the 1AR carboxyl terminus being the key determinants of the interaction. In cells, the association of full-length 1AR 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 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 1AR. Further cellular experiments revealed that MAGI-2 has no effect on 1AR oligomerization but does promote association of 1AR with the cytoplasmic signaling protein -catenin, a known MAGI-2 binding partner. These data reveal that MAGI-2 is a specific 1AR binding partner that modulates 1AR function and facilitates the physical association of the 1AR with intracellular proteins involved in signal transduction and synaptic regulation.

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تاریخ انتشار 2001