Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells

Pflügers Archiv : European journal of physiology
Lia BakiDiomedes E Logothetis

Abstract

We previously reported that co-expression of the Gi-coupled metabotropic glutamate receptor 2 (mGlu2R) and the Gq-coupled serotonin (5-HT) 2A receptor (2AR) in Xenopus oocytes (Fribourg et al. Cell 147:1011-1023, 2011) results in inverse cross-signaling, where for either receptor, strong agonists suppress and inverse agonists potentiate the signaling of the partner receptor. Importantly, through this cross-signaling, the mGlu2R/2AR heteromer integrates the actions of psychedelic and antipsychotic drugs. To investigate whether mGlu2R and 2AR can cross-signal in mammalian cells, we stably co-expressed them in HEK293 cells along with the GIRK1/GIRK4 channel, a reporter of Gi and Gq signaling activity. Crosstalk-positive clones were identified by Fura-2 calcium imaging, based on potentiation of 5-HT-induced Ca(2+) responses by the inverse mGlu2/3R agonist LY341495. Cross-signaling from both sides of the complex was confirmed in representative clones by using the GIRK channel reporter, both in whole-cell patch-clamp and in fluorescence assays using potentiometric dyes, and further established by competition binding assays. Notably, only 25-30 % of the clones were crosstalk-positive. The crosstalk-positive phenotype correlated with (...Continue Reading

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Citations

Jun 1, 2016·Frontiers in Pharmacology·Carolina MuguruzaLuis F Callado
Nov 5, 2016·Neuropharmacology·Luisa IacovelliFerdinando Nicoletti
Feb 14, 2017·PLoS Computational Biology·Miguel FribourgVladimir Brezina
Mar 30, 2018·Nature Communications·Gemma NavarroSergi Ferré
Sep 14, 2018·Psychopharmacology·Kelsey S HideshimaJavier González-Maeso
Oct 22, 2020·Science Signaling·Rudy ToneattiJavier González-Maeso
Feb 27, 2019·ACS Chemical Neuroscience·Urjita H Shah, Javier González-Maeso
May 1, 2019·ACS Chemical Neuroscience·Barbara ChruścickaHarriët Schellekens

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