Research ArticleGPCR SIGNALING

Interclass GPCR heteromerization affects localization and trafficking

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Science Signaling  20 Oct 2020:
Vol. 13, Issue 654, eaaw3122
DOI: 10.1126/scisignal.aaw3122

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GPCR heteromers go intracellular together

Whereas some GPCRs (such as the metabotropic glutamate mGluR2 receptor) are largely found on the cell surface, others (such as the serotonin 5-HT2A receptor) are mainly localized in intracellular compartments. Toneatti et al. found that 5-HT2A receptors promoted the internalization of cell surface mGluR2 in unstimulated cells, an effect that required the heteromerization of these two GPCRs. The intracellular localization of mGluR2 was increased by 5-HT2A receptor stimulation but decreased by mGluR2 activation or exposure to clozapine, an inverse antagonist of 5-HT2A receptors. Neurons from mice lacking 5-HT2A receptors showed greater surface localization of mGluR2 compared to those from wild-type mice. Thus, 5-HT2A receptors influence the intracellular localization of mGluR2 in a manner dependent on the activation state of the receptors in the heteromer.

Abstract

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-HT2A receptors (5-HT2ARs) 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-HT2AR was primarily localized within intracellular compartments, and coexpression of 5-HT2AR with mGluR2 increased the intracellular distribution of the otherwise plasma membrane–localized mGluR2. Agonists for either 5-HT2AR or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT2AR–mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT2AR blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT2AR and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT2AR–mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT2AR–dependent effects on mGluR2 subcellular distribution. The expression of 5-HT2AR 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.

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