Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84
GPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2023
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| _version_ | 1797112698900578304 |
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| author | Luscombe, VB Baena Lopez, LA Bataille, CJR Russell, AJ Greaves, DR |
| author_facet | Luscombe, VB Baena Lopez, LA Bataille, CJR Russell, AJ Greaves, DR |
| author_sort | Luscombe, VB |
| collection | OXFORD |
| description | GPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that phenocopy the response of primary cells in a label-free cell electrical impedance (CEI) sensing system that measures cell morphology and adhesion. We then investigated the signalling profile and membrane localisation of GPR84 upon treatment with 6-OAU and DL-175, two agonists known to differentially influence immune cell function. When compared to 6-OAU, DL-175 was found to exhibit a delayed impedance response, a delayed and suppressed activation of Akt, which together correlated with an impaired ability to internalise GPR84 from the plasma membrane. The signalling differences were transient and occurred only at early time points in the low expressing cell lines, highlighting the importance of receptor number and kinetic readouts when evaluating signalling bias. Our findings open new ways to understand GPR84 signalling and evaluate the effect of newly developed agonists. |
| first_indexed | 2024-03-07T08:27:33Z |
| format | Journal article |
| id | oxford-uuid:604a5f5a-7687-44bc-82a4-7bab82e2c2a7 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:27:33Z |
| publishDate | 2023 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:604a5f5a-7687-44bc-82a4-7bab82e2c2a72024-02-26T14:38:45ZKinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:604a5f5a-7687-44bc-82a4-7bab82e2c2a7EnglishSymplectic ElementsElsevier2023Luscombe, VBBaena Lopez, LABataille, CJRRussell, AJGreaves, DRGPR84 is an orphan G-protein coupled receptor (GPCR) linked to inflammation. Strategies targeting GPR84 to prevent excessive inflammation in disease are hampered by a lack of understanding of its precise functional role. We have developed heterologous cell lines with low GPR84 expression levels that phenocopy the response of primary cells in a label-free cell electrical impedance (CEI) sensing system that measures cell morphology and adhesion. We then investigated the signalling profile and membrane localisation of GPR84 upon treatment with 6-OAU and DL-175, two agonists known to differentially influence immune cell function. When compared to 6-OAU, DL-175 was found to exhibit a delayed impedance response, a delayed and suppressed activation of Akt, which together correlated with an impaired ability to internalise GPR84 from the plasma membrane. The signalling differences were transient and occurred only at early time points in the low expressing cell lines, highlighting the importance of receptor number and kinetic readouts when evaluating signalling bias. Our findings open new ways to understand GPR84 signalling and evaluate the effect of newly developed agonists. |
| spellingShingle | Luscombe, VB Baena Lopez, LA Bataille, CJR Russell, AJ Greaves, DR Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title | Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title_full | Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title_fullStr | Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title_full_unstemmed | Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title_short | Kinetic insights into agonist-dependent signalling bias at the pro-inflammatory G-protein coupled receptor GPR84 |
| title_sort | kinetic insights into agonist dependent signalling bias at the pro inflammatory g protein coupled receptor gpr84 |
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