Open AccessInterclass GPCR heteromerization affects localization and trafficking
Author(s) -
Rudy Toneatti,
Jong M. Shin,
Urjita H. Shah,
Carl R. Mayer,
Justin M. Saunders,
Miguel Fribourg,
Paul T. Arsenovic,
William G.M. Janssen,
Stuart C. Sealfon,
Juan F. López-Giménez,
Deanna L. Benson,
Daniel E. Conway,
Javier González-Maeso
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.aaw3122
Subject(s) - metabotropic glutamate receptor 2 , g protein coupled receptor , microbiology and biotechnology , intracellular , endosome , biology , metabotropic glutamate receptor , chemistry , receptor , biochemistry , signal transduction , glutamate receptor
Membrane trafficking processes regulate G protein-coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT 2A receptors (5-HT 2A Rs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT 2A R was primarily localized within intracellular compartments, and coexpression of 5-HT 2A R with mGluR2 increased the intracellular distribution of the otherwise plasma membrane-localized mGluR2. Agonists for either 5-HT 2A R or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT 2A R-mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT 2A R blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT 2A R and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT 2A R-mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT 2A R-dependent effects on mGluR2 subcellular distribution. The expression of 5-HT 2A R also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting.