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

  • Lia Baki
  • Miguel Fribourg
  • Jason Younkin
  • Jose Miguel Eltit
  • Jose L. Moreno
  • Gyu Park
  • Zhanna Vysotskaya
  • Adishesh Narahari
  • Stuart C. Sealfon
  • Javier Gonzalez-Maeso
  • Diomedes E. Logothetis
Ion channels, receptors and transporters


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 Ca2+ 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 (a) increased colocalization of the two receptors at the cell surface, (b) lower density of mGlu2R binding sites and higher density of 2AR binding sites in total membrane preparations, and (c) higher ratios of mGlu2R/2AR normalized surface protein expression. Consistent with our results in Xenopus oocytes, a combination of ligands targeting both receptors could elicit functional crosstalk in a crosstalk-negative clone. Crosstalk-positive clones can be used in high-throughput assays for identification of antipsychotic drugs targeting this receptor heterocomplex.


G protein-coupled receptor (GPCR) Metabotropic glutamate 2 (mGlu2) receptor 5-HT2A receptor Cross-signaling Calcium intracellular release Membrane potential probes Mammalian cells 



The authors wish to thank Dr. Taihao Jin (University of California, San Francisco) for developing an automated program to read fluorescent data from 96-well microplates in a Flex Station 3 reader, Dr Clive M. Baumgarten (Virginia Commonwealth University) for kindly offering access to his patch-clamp rigs, Dr George Liapakis (University of Crete, Greece) for preliminary binding experiments in the clonal cell lines, Drs Carlos A. Villalba-Galea (Virginia Commonwealth University) and Qiong Yao Tang (Xuzhou Medical College, Xuzhou, Jiangsu Province, China) for help with electrophysiology experiments, and Junghoon Ha for analysis and with the presentation of Fig. S3. We also thank all members of the Logothetis lab for critical feedback on the work and the manuscript. We acknowledge Heikki Vaananen and Nada Marjanovic for technical support and the Icahn School of Medicine at Mount Sinai Quantitative PCR Core Facility.

This work was supported by the National Institutes of Health grants R01HL59949 and R01 HL090882 to D.E.L, R01MH084894 to J.G-M, and T32 MH096678 training grant to M.F.

Supplementary material

424_2015_1780_MOESM1_ESM.pdf (313 kb)
ESM 1 Sample traces from whole-cell patch-clamp recordings of GIRK1/4 currents in HEK/GIRK clone 31 in response to 100 μM GTPγS (a) and HEK/GIRK/mGlu 2 R clone 59 in response to 100 μM Glu (b). Whole-cell patch-clamp current recordings were performed as detailed in the Methods. Application of BaCl2 abolished the current (PDF 313 kb)
424_2015_1780_MOESM2_ESM.avi (10.3 mb)
ESM 2 Time course of calcium mobilization in response to 5-HT in HEK/GIRK/mGlu2R/2AR clone 106, reported by the calcium indicator Fura-2 (AVI 10.3 mb)
424_2015_1780_MOESM3_ESM.avi (3.6 mb)
ESM 3 Time course of calcium mobilization in response to 5-HT in HEK/GIRK/mGlu2R/2AR clone 146, reported by the calcium indicator Fura-2 (AVI 3.62 mb)
424_2015_1780_MOESM4_ESM.pdf (4.8 mb)
ESM 4 HEK/GIRK/mGlu 2 R/2AR clones 3 and 92 displayed unexpected responses. a,b Summary of responses of FURA-2-loaded cells from clone 3 (a) or clone 92 (b) to 20-50 nM 5-HT ± 100 μM of LY34, analyzed as indicated in the legend to Fig. 2. The crosstalk-positive clone 80 and the crosstalk-negative clone 45 have been included for reference. c Degrees of colocalization of mGlu2R and 2AR in clones 3 and 92 (grey bars), determined as described in the legend to Fig. 3, are shown together with the corresponding degrees in the crosstalk-positive clone 80 (black bar) and the crosstalk-negative clone 45 (white bar). d Ratios of normalized (protein/mRNA) mGlu2R to normalized (protein/mRNA) 2AR for clones 3 and 92 (grey bars) are shown together with the corresponding ratios in the crosstalk-positive clone 80 (black bars) and the crosstalk-negative clone 45 (white bars).e Crosstalk-positive and crosstalk-negative clones segregate in two distinct groups when their average mGlu2R protein/mRNA ratio is plotted against their average 2AR protein/mRNA ratio. f Summary of responses of clone 92 (N = 5) to application of Glu (20 μM) followed by addition of Paliperidone (50 μM), measured by the potentiometric dye FLIPR Blue as described in the legend of Fig. 8. Responses from the crosstalk-positive clone 80 (N = 19) and the control clone 59 (N = 16) are shown for reference (PDF 4.83 mb)
424_2015_1780_MOESM5_ESM.pdf (1003 kb)
ESM 5 Representative current traces from whole-cell patch-clamp recordings of GIRK currents for the positive results shown in Fig. 6 for clones HEK/GIRK/mGlu2R/2AR clones 80 and 45. (a) 5-HT (20 nM), followed by 5-HT (20 nM) + LY34 (100 μM) for clone 80, (b) Glutamate (Glu, 500 nM), followed by Glu (500 nM) + Paliperidone (100 μM) (Glu + Pal) for clone 80, (c) LY37 (50 nM), followed by LY37 (50 nM) + Pal (100 μM). Gq activity for clone 45. Since the agonist concentrations used were below the EC50 values, responses showed large fluctuations, thus running averages of the traces were produced using the Origin software (OriginLab Corporation) and displayed in the figure (PDF 0.97 mb)
424_2015_1780_MOESM6_ESM.avi (30.1 mb)
ESM 6 Time course of changes in fluorescence in response to the sequential application of Glu and Glu + Tertiapin Q, recorded by epifluorescence microscopy in HLB 021-152- loaded cells from HEK/GIRK/mGlu2R/2AR clone 106. Pseudocolor has been used to facilitate visualization of the small changes in fluorescence (see Fig. 7), associated with this type of fluorescent potentiometric probes (AVI 30 mb)
424_2015_1780_MOESM7_ESM.avi (32.2 mb)
ESM 7 Time course of changes in fluorescence in response to sequential application of Glu (50 μM) and Glu + Tertiapin Q (100 nM), recorded by epifluorescence microscopy in HLB 021-152- loaded cells from HEK/GIRK/mGlu2R clone 3. The same pseudocolor used for Video 3 has been used here to facilitate comparison (AVI 32.2 mb)
424_2015_1780_MOESM8_ESM.pdf (2.4 mb)
ESM 8 Sample traces of Gi- dependent changes in GIRK channel activity reported by the potentiometric dye HLB 021-152 and recorded by epifluorescence microscopy. a,b Changes in fluorescence in response to sequential application of Glu (50 μM) and Glu + Tertiapin Q (100 nM) as recorded by epifluorescence microscopy in HLB 021-152- loaded cells from the HEK/GIRK/mGlu2R/2AR clone 106 (a) and from the parental HEK/GIRK clone 31 (b). Each line corresponds to the response of a single cell (PDF 2.40 mb)
424_2015_1780_MOESM9_ESM.avi (15.7 mb)
ESM 9 Time course of changes in fluorescence in response to sequential application of Glu (50 μM) and Glu + 5-HT (1 μM), recorded by epifluorescence microscopy in HLB 021-152- loaded cells from HEK/GIRK/mGlu2R/2AR clone 106. Pseudocolor has been used to facilitate visualization of the small changes in fluorescence (see Fig. 7b) (AVI 15.6 mb)
424_2015_1780_MOESM10_ESM.pdf (1.8 mb)
ESM 10 Sample traces of Gi- and Gq- dependent changes in GIRK channel activity reported by the potentiometric dye HLB 021-152 and recorded by epifluorescence microscopy. Changes in fluorescence in response to sequential application of Glu (50 μM) and Glu + 5-HT (1 μM) as recorded by epifluorescence microscopy in HLB 021-152- loaded cells from the HEK/GIRK/mGlu2R/2AR clone 106. Each line corresponds to the response of a single cell (PDF 1.75 mb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Lia Baki
    • 1
  • Miguel Fribourg
    • 2
  • Jason Younkin
    • 1
  • Jose Miguel Eltit
    • 1
  • Jose L. Moreno
    • 3
  • Gyu Park
    • 1
  • Zhanna Vysotskaya
    • 1
  • Adishesh Narahari
    • 1
  • Stuart C. Sealfon
    • 2
    • 4
    • 5
  • Javier Gonzalez-Maeso
    • 1
    • 2
    • 3
    • 5
  • Diomedes E. Logothetis
    • 1
  1. 1.Department of Physiology and BiophysicsVirginia Commonwealth University School of MedicineRichmondUSA
  2. 2.Department of NeurologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA

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