beta(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.

The beta (1)-adrenergic receptor (beta (1)AR) is known to be localized to s ynapses and to modulate synaptic plasticity in many brain regions, but the molecular mechanisms determining beta (1)AR subcellular localization are no t fully understood. Using overlay and pull-down techniques, we found that t he beta (1)AR carboxyl terminus associates with MAGI-2 (membrane-associated guanylate kinase inverted-2), a protein also known as S-SCAM (synaptic sca ffolding molecule). MAGI-2 is a multidomain scaffolding protein that contai ns nine potential protein-protein interaction modules, including 6 PDZ doma ins, 2 WW domains, and a guanylate kinase-like domain. The beta (1)AR carbo xyl terminus binds with high affinity to the first PDZ domain of MAGI-2, wi th the last few amino acids of the beta (1)AR carboxyl terminus being the k ey determinants of the interaction. In cells, the association of full-lengt h beta (1)AR with MAGI-2 occurs constitutively and is enhanced by agonist s timulation of the receptor, as assessed by both co-immunoprecipitation expe riments and immunofluorescence co-localization studies. Agonist-induced int ernalization of the beta (1)AR is markedly increased by co-expression with MAGI-2. Strikingly, this result is the opposite of the effect of co-express ion with PSD-95, a previously reported binding partner of the beta (1)AR. F urther cellular experiments revealed that MAGI-2 has no effect on beta (1)A R oligomerization but does promote association of beta (1)AR with the cytop lasmic signaling protein beta -catenin, a known MAGI-2 binding partner. The se data reveal that MAGI-2 is a specific beta (1)AR binding partner that mo dulates beta (1)AR function and facilitates the physical association of the beta (1)AR with intracellular proteins involved in signal transduction and synaptic regulation.