Proton-Sensing GPCRs in Health and Disease
Abstract
:1. Proton-Sensing GPCRs—Structural Features and Physiology
2. GPR4
3. TDAG8 (GPR65)
4. OGR1 (GPR68)
5. G2A (GPR132)
6. Outlook
6.1. Modulating and Targeting the Four GPCRs
6.2. Expanding the Group of Proton-Sensing GPCRs
6.3. Proton-Sensing GPCRs in Persistent Pain States
Funding
Conflicts of Interest
References
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Agonist | EC50 or Active Concentration | Test System and/or Consequence | Refs |
Protons | pH 7.6–5.6 | pH-dependent cAMP assay in various transfected cell lines | [1,62,63] |
Antagonist | IC50 or Active Concentration | Test System and Consequence | Refs |
Compound 3b (dibenzazepine derivative) | IC50: 67 nM | HEK-293-cell-based Luciferase assay, mouse myocardial infarction model | [66] |
NE 52-QQ57 (compound 13 in reference) | IC50: 70 nM | pH-dependent cAMP assay in HeLa and HEK-293 cells, angiogenesis growth factor model, CFA-model for inflammatory pain | [69] |
Compound 39c (imidazopyridine derivative) | IC50: 110 nM | pH-dependent cAMP assay in HeLa and HEK-293 cells, mouse VEGF-angiogenesis model, rat antigen-induced arthritis model, CFA-induced inflammatory pain | [70] |
Agonist | EC50 or Active Concentration | Test System and/or Consequence | Refs |
Protons | pH 7.2–5.7 | pH-dependent cAMP assay in stably TDAG8-transfected CHO cells | [42] |
Psychosine | EC50: 3.4 µM (cAMP assay) | cAMP assay, calcium-mobilization in TDAG8-transfected HEK-293 cells | [72] |
BTB09089 | active concentration > 5 µM | cAMP assay in splenocytes | [74] |
Positive Allosteric Modulators (PAMs) | IC50 or Active Concentration | Test System and Consequence | Refs |
ZINC13684400 | micromolar range | library of drugs and compounds tested in a yeast TDAG8 expressing system, using cAMP production as readout | [11] |
Negative Allosteric Modulators (NAMs) | IC50 or Active Concentration | Test System and Consequence | Refs |
ZINC62678696 | micromolar range | library of drugs and compounds tested in a yeast TDAG8 expressing system, using cAMP production as readout | [11] |
Agonist | EC50 or Active Concentration | Test System and/or Consequence | Refs |
Protons | pH 7.8–5.6, maximum activity at pH 6.8 | pH-dependent cAMP assay in various cells | [1,105] |
3,5-disubstituted isoxazoles | micromolar range | Calcium transients in transfected Notch-activated epicardium-derived cells (NECs) | [90] |
CART(42–89)(9–28) shorter variant of cocaine- and amphetamine-regulated transcript | EC50: 1 µM | Identified via:
| [103] |
steocrin-derived peptide (115–133) | EC50: 380 nM | [103] | |
pro-opiomelanocortin-derived peptide (141–162) | EC50: 1.3 µM | [103] | |
Positive Allosteric Modulators (PAMs) | IC50 or Active Concentration | Test System and Consequence | Refs |
ogerin | Kb: ~10 µM, requires the presence of protons | library of drugs and compounds tested in a yeast OGR1 expressing system, using cAMP production as readout | [11] |
lorazepam | non-selective, micromolar range | [48] | |
MS48107 | Kb: ~1–10 µM | cAMP assay in transfected HEK-293 cells. | [104] |
Agonist | EC50 or Active Concentration | Test System and/or Consequence | Refs |
Protons | pH 8.2–6.6 | Gq-activation, generation of IP3 in NIH-3T3 fibroblasts | [5] |
9S-HODE | EC50: ~0.5 µM [118] | [Ca2+]i-increase in stably G2A-transfected CHO cells | [39,118] |
11-HETE | EC50: ~1 µM [118] | [Ca2+]i-increase in stably G2A-transfected CHO cells | [39,118] |
N-palmitoylglycine | EC50: ~800 nM, similar for human- rat- and mouse-G2A | yeast assay and β-arrestin association assay (in HEK-293 cells) | [113] |
N-linoleoylglycine | EC50: ~800 nM, similar for human- rat- and mouse-G2A | yeast assay and β-arrestin association assay (in HEK-293 cells) | [113] |
ONC212 (second-generation imipridone) | ~400 nM | PathHunter β-arrestin association assay in HEK-293 cells | [117] |
11,12-EET | ~10 µM | PathHunter β-arrestin association assay in HEK-293 cells | [40] |
9,10-EpOME | ~10 µM | PathHunter β-arrestin association assay in HEK-293 cells | [40] |
Antagonist | IC50 or Active Concentration | Test System and Consequence | Refs |
Lysophosphatidylcholine (LPC) | ~10 µM | inhibits Gq-dependent, generation of IP3 in NIH-3T3 fibroblasts | [5] |
Telmisartan | ~10 µM | β-arrestin association assay in HEK-293 cells | [113] |
GSK1820795A | ~1 µM | β-arrestin association assay in HEK-293 cells | [113] |
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Sisignano, M.; Fischer, M.J.M.; Geisslinger, G. Proton-Sensing GPCRs in Health and Disease. Cells 2021, 10, 2050. https://doi.org/10.3390/cells10082050
Sisignano M, Fischer MJM, Geisslinger G. Proton-Sensing GPCRs in Health and Disease. Cells. 2021; 10(8):2050. https://doi.org/10.3390/cells10082050
Chicago/Turabian StyleSisignano, Marco, Michael J. M. Fischer, and Gerd Geisslinger. 2021. "Proton-Sensing GPCRs in Health and Disease" Cells 10, no. 8: 2050. https://doi.org/10.3390/cells10082050
APA StyleSisignano, M., Fischer, M. J. M., & Geisslinger, G. (2021). Proton-Sensing GPCRs in Health and Disease. Cells, 10(8), 2050. https://doi.org/10.3390/cells10082050