Interclass GPCR Heteromerization Affects Localization and Trafficking

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2020 Oct 21

PMID 33082287

Citations 23

Authors

Rudy Toneatti

Jong M Shin

Urjita H Shah

Carl R Mayer

Justin M Saunders

Miguel Fribourg

Paul T Arsenovic

William G Janssen

Stuart C Sealfon

Juan F Lopez-Gimenez

Deanna L Benson

Daniel E Conway

Javier Gonzalez-Maeso

Affiliations

Soon will be listed here.

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

Citing Articles

Type I gamma phosphatidylinositol phosphate 5-kinase i5 controls cell sensitivity to interferon.

Ghosh C, Kakar R, Hoyle R, Liu Z, Guo C, Li J Dev Cell. 2024; 59(8):1028-1042.e5.

PMID: 38452758 PMC: 11043016. DOI: 10.1016/j.devcel.2024.02.005.

Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations.

Palmisano V, Agnorelli C, Fagiolini A, Erritzoe D, Nutt D, Faraji S Biochemistry. 2024; .

PMID: 38324395 PMC: 10882957. DOI: 10.1021/acs.biochem.3c00598.

Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats.

Reinwald J, Schmitz C, Skorodumov I, Kuchar M, Weber-Fahr W, Spanagel R Transl Psychiatry. 2023; 13(1):392.

PMID: 38097569 PMC: 10721862. DOI: 10.1038/s41398-023-02690-1.

Modulation of DOM-Induced Head-Twitch Response by mGluR2 Agonist/Inverse Agonist is Associated with 5-HTR-Mediated G Signaling Pathway.

Gao H, Liu X, Xie L, Tan B, Su R Neurochem Res. 2023; 49(3):636-648.

PMID: 37989895 DOI: 10.1007/s11064-023-04055-y.

Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics.

Jaster A, Gonzalez-Maeso J Mol Psychiatry. 2023; 28(9):3595-3612.

PMID: 37759040 PMC: 11078317. DOI: 10.1038/s41380-023-02274-x.

References

Sorkin A, Von Zastrow M . Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol. 2009; 10(9):609-22. PMC: 2895425. DOI: 10.1038/nrm2748. View

Kotowski S, Hopf F, Seif T, Bonci A, Von Zastrow M . Endocytosis promotes rapid dopaminergic signaling. Neuron. 2011; 71(2):278-90. PMC: 3417347. DOI: 10.1016/j.neuron.2011.05.036. View

Hamor P, Sirova J, Palenicek T, Zaniewska M, Bubenikova-Valesova V, Schwendt M . Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: Comparison to chronic phencyclidine and MK-801. Pharmacol Biochem Behav. 2018; 175:89-100. PMC: 6756482. DOI: 10.1016/j.pbb.2018.09.007. View

Jakab R, Goldman-Rakic P . 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites. Proc Natl Acad Sci U S A. 1998; 95(2):735-40. PMC: 18490. DOI: 10.1073/pnas.95.2.735. View

Ferre S, Casado V, Devi L, Filizola M, Jockers R, Lohse M . G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev. 2014; 66(2):413-34. PMC: 3973609. DOI: 10.1124/pr.113.008052. View

Gonzalez-Maeso J, Sealfon S . Psychedelics and schizophrenia. Trends Neurosci. 2009; 32(4):225-32. DOI: 10.1016/j.tins.2008.12.005. View

Bajar B, Wang E, Zhang S, Lin M, Chu J . A Guide to Fluorescent Protein FRET Pairs. Sensors (Basel). 2016; 16(9). PMC: 5038762. DOI: 10.3390/s16091488. View

Moreno J, Muguruza C, Umali A, Mortillo S, Holloway T, Pilar-Cuellar F . Identification of three residues essential for 5-hydroxytryptamine 2A-metabotropic glutamate 2 (5-HT2A·mGlu2) receptor heteromerization and its psychoactive behavioral function. J Biol Chem. 2012; 287(53):44301-19. PMC: 3531745. DOI: 10.1074/jbc.M112.413161. View

de la Fuente Revenga M, Ibi D, Cuddy T, Toneatti R, Kurita M, Ijaz M . Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity. Neuropsychopharmacology. 2018; 44(2):443-454. PMC: 6300555. DOI: 10.1038/s41386-018-0143-4. View

10.

Poulie C, Liu N, Jensen A, Bunch L . Design, Synthesis, and Pharmacological Characterization of Heterobivalent Ligands for the Putative 5-HT/mGlu Receptor Complex. J Med Chem. 2020; 63(17):9928-9949. DOI: 10.1021/acs.jmedchem.0c01058. View

11.

Xue L, Rovira X, Scholler P, Zhao H, Liu J, Pin J . Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. Nat Chem Biol. 2014; 11(2):134-40. DOI: 10.1038/nchembio.1711. View

12.

Ibi D, de la Fuente Revenga M, Kezunovic N, Muguruza C, Saunders J, Gaitonde S . Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Nat Neurosci. 2017; 20(9):1247-1259. PMC: 5675106. DOI: 10.1038/nn.4616. View

13.

Von Zastrow M, Williams J . Modulating neuromodulation by receptor membrane traffic in the endocytic pathway. Neuron. 2012; 76(1):22-32. PMC: 3496082. DOI: 10.1016/j.neuron.2012.09.022. View

14.

Kasai R, Suzuki K, Prossnitz E, Koyama-Honda I, Nakada C, Fujiwara T . Full characterization of GPCR monomer-dimer dynamic equilibrium by single molecule imaging. J Cell Biol. 2011; 192(3):463-80. PMC: 3101103. DOI: 10.1083/jcb.201009128. View

15.

Riad M, Wu C, Singh S, Descarries L . Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol. 1999; 409(2):187-209. DOI: 10.1002/(sici)1096-9861(19990628)409:2<187::aid-cne2>3.0.co;2-p. View

16.

Chaudhry F, Lehre K, van Lookeren Campagne M, Ottersen O, Danbolt N, Storm-Mathisen J . Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry. Neuron. 1995; 15(3):711-20. DOI: 10.1016/0896-6273(95)90158-2. View

17.

Milligan G . The role of dimerisation in the cellular trafficking of G-protein-coupled receptors. Curr Opin Pharmacol. 2009; 10(1):23-9. DOI: 10.1016/j.coph.2009.09.010. View

18.

Berg K, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke W . Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol. 1998; 54(1):94-104. View

19.

Smith T, Li J, Dores M, Trejo J . Protease-activated receptor-4 and purinergic receptor P2Y12 dimerize, co-internalize, and activate Akt signaling via endosomal recruitment of β-arrestin. J Biol Chem. 2017; 292(33):13867-13878. PMC: 5566538. DOI: 10.1074/jbc.M117.782359. View

20.

Tashiro A, Yuste R . Structure and molecular organization of dendritic spines. Histol Histopathol. 2003; 18(2):617-34. DOI: 10.14670/HH-18.617. View