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http://hdl.handle.net/1942/42682
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DC Field | Value | Language |
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dc.contributor.author | VAN VEGGEL, Lieve | - |
dc.contributor.author | Mocking, Tamara A. M. | - |
dc.contributor.author | Sijben, Hubert J. | - |
dc.contributor.author | Liu, Rongfang | - |
dc.contributor.author | Gonzalez, Marina Gorostiola | - |
dc.contributor.author | Dilweg, Majlen A. | - |
dc.contributor.author | Royakkers, Jeroen | - |
dc.contributor.author | Li, Anna | - |
dc.contributor.author | Kumar, Vijay | - |
dc.contributor.author | Dong, Yin Yao | - |
dc.contributor.author | Bullock, Alex | - |
dc.contributor.author | Sauer, David B. | - |
dc.contributor.author | Dilien , Hanne | - |
dc.contributor.author | van Westen, Gerard J. P. | - |
dc.contributor.author | Schreiber, Rudy | - |
dc.contributor.author | Heitman, Laura H. | - |
dc.contributor.author | VANMIERLO, Tim | - |
dc.date.accessioned | 2024-03-26T09:18:28Z | - |
dc.date.available | 2024-03-26T09:18:28Z | - |
dc.date.issued | 2024 | - |
dc.date.submitted | 2024-03-26T07:42:42Z | - |
dc.identifier.citation | ACS Chemical Neuroscience, | - |
dc.identifier.uri | http://hdl.handle.net/1942/42682 | - |
dc.description.abstract | Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target. | - |
dc.description.sponsorship | Funding Parts of this research were performed within the RESOLUTE and EUbOpen projects. RESOLUTE and EUbOpen have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement Nos. 777372 and 875510, respectively. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA. This article reflects only the authors’ views and neither IMI nor the European Union and EFPIA are responsible for any use that may be made of the information contained therein. This project was also partially funded by the FWO (1S34321N) and the Fondation Charcot Stichting. ACKNOWLEDGMENTS We would like to thank Prof. Fontana and her team for their help and guidance throughout our scientific efforts to replicate their in vitro findings regarding the effects of GT949 and for kindly providing us with their homology model of EAAT2, including their identified binding pocket of GT949. | - |
dc.language.iso | en | - |
dc.publisher | AMER CHEMICAL SOC | - |
dc.rights | Open access. This article is licensed under CC-BY 4.0 | - |
dc.subject.other | EAAT2 | - |
dc.subject.other | GT949 | - |
dc.subject.other | radioligand uptake | - |
dc.subject.other | glutamate | - |
dc.subject.other | transport | - |
dc.subject.other | modulation | - |
dc.title | Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays | - |
dc.type | Journal Contribution | - |
local.format.pages | 8 | - |
local.bibliographicCitation.jcat | A1 | - |
dc.description.notes | Vanmierlo, T (corresponding author), Hasselt Univ, Fac Med & Life Sci, BIOMED Biomed Res Inst, Dept Neurosci, B-3590 Hasselt, Belgium.; Vanmierlo, T (corresponding author), Maastricht Univ, European Grad Sch Neurosci, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol,Div Translat Neurosci, NL-6200 Maastricht, Netherlands.; Vanmierlo, T (corresponding author), Univ MS Ctr UMSC, B-3900 Hasselt, Belgium. | - |
dc.description.notes | tim.vanmierlo@uhasselt.be | - |
local.publisher.place | 1155 16TH ST, NW, WASHINGTON, DC 20036 USA | - |
local.type.refereed | Refereed | - |
local.type.specified | Article | - |
local.bibliographicCitation.status | Early view | - |
local.type.programme | H2020 | - |
local.relation.h2020 | 777372+ 875510 | - |
dc.identifier.doi | 10.1021/acschemneuro.3c00731 | - |
dc.identifier.isi | 001184190800001 | - |
dc.contributor.orcid | Kumar, Vijay/0000-0002-0008-9944 | - |
local.provider.type | wosris | - |
local.description.affiliation | [van Veggel, Lieve; Vanmierlo, Tim] Hasselt Univ, Fac Med & Life Sci, BIOMED Biomed Res Inst, Dept Neurosci, B-3590 Hasselt, Belgium. | - |
local.description.affiliation | [van Veggel, Lieve; Gonzalez, Marina Gorostiola; Vanmierlo, Tim] Maastricht Univ, European Grad Sch Neurosci, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol,Div Translat Neurosci, NL-6200 Maastricht, Netherlands. | - |
local.description.affiliation | [van Veggel, Lieve; Vanmierlo, Tim] Univ MS Ctr UMSC, B-3900 Hasselt, Belgium. | - |
local.description.affiliation | [Mocking, Tamara A. M.; Sijben, Hubert J.; Liu, Rongfang; Dilweg, Majlen A.; van Westen, Gerard J. P.; Heitman, Laura H.] Leiden Univ, Leiden Acad Ctr Drug Res LACDR, Div Drug Discovery & Safety, NL-2333 Leiden, Netherlands. | - |
local.description.affiliation | [Schreiber, Rudy] Maastricht Univ, Fac Psychol & Neurosci, Sect Psychopharmacol Neuropsychol & Psychopharmaco, NL-6200 Maastricht, Netherlands. | - |
local.description.affiliation | [Royakkers, Jeroen; Dilien, Hanne] Maastricht Univ, Fac Sci & Engn, Sensor Engn Dept, NL-6200 Maastricht, Netherlands. | - |
local.description.affiliation | [Li, Anna; Kumar, Vijay; Bullock, Alex; Sauer, David B.] Univ Oxford, Ctr Med Discovery, Nuffield Dept Med, Oxford OX3 7BN, England. | - |
local.description.affiliation | [Dong, Yin Yao] Univ Oxford, Weatherall Inst Mol Med, Nuffield Dept Clin Neurosci, Oxford OX3 7BN, England. | - |
local.description.affiliation | [Heitman, Laura H.] Oncode Inst, NL-2333 Leiden, Netherlands. | - |
local.uhasselt.international | yes | - |
item.fullcitation | VAN VEGGEL, Lieve; Mocking, Tamara A. M.; Sijben, Hubert J.; Liu, Rongfang; Gonzalez, Marina Gorostiola; Dilweg, Majlen A.; Royakkers, Jeroen; Li, Anna; Kumar, Vijay; Dong, Yin Yao; Bullock, Alex; Sauer, David B.; Dilien , Hanne; van Westen, Gerard J. P.; Schreiber, Rudy; Heitman, Laura H. & VANMIERLO, Tim (2024) Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays. In: ACS Chemical Neuroscience,. | - |
item.contributor | VAN VEGGEL, Lieve | - |
item.contributor | Mocking, Tamara A. M. | - |
item.contributor | Sijben, Hubert J. | - |
item.contributor | Liu, Rongfang | - |
item.contributor | Gonzalez, Marina Gorostiola | - |
item.contributor | Dilweg, Majlen A. | - |
item.contributor | Royakkers, Jeroen | - |
item.contributor | Li, Anna | - |
item.contributor | Kumar, Vijay | - |
item.contributor | Dong, Yin Yao | - |
item.contributor | Bullock, Alex | - |
item.contributor | Sauer, David B. | - |
item.contributor | Dilien , Hanne | - |
item.contributor | van Westen, Gerard J. P. | - |
item.contributor | Schreiber, Rudy | - |
item.contributor | Heitman, Laura H. | - |
item.contributor | VANMIERLO, Tim | - |
item.accessRights | Open Access | - |
item.fulltext | With Fulltext | - |
crisitem.journal.issn | 1948-7193 | - |
crisitem.journal.eissn | 1948-7193 | - |
Appears in Collections: | Research publications |
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File | Description | Size | Format | |
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van-veggel-et-al-2024-still-in-search-for-an-eaat-activator-gt949-does-not-activate-eaat2-nor-eaat3-in-impedance-and.pdf | Early view | 2.56 MB | Adobe PDF | View/Open |
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