Bitter Taste Receptor T2R4 Mediated Inactivation of Rac1 GTPase in Response to Quinine
Bibliographic record
Abstract
Rac1 is a member of the Rho family of low molecular mass GTP binding proteins (GTPases). It regulates the dynamics of actin cytoskeleton by causing membrane ruffling, chemotaxis, and lamellipodia formation. Rac1 has been recently implicated in cancer metastasis and progression. As is the case with other GTPases, Rac1 cycles between the active GTP‐bound form and the inactive GDP‐bound form. This step is facilitated by a variety of Guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). T2R4 is a bitter taste receptor that belongs to the GPCR (G protein‐coupled receptor) family of membrane proteins. In addition to mediating bitter taste sensations from the tongue, T2R4 and other T2Rs have been recently found in tissues other than the oral cavity e.g. nasal epithelium, airways, brain, gastrointestinal tract and male reproductive system suggesting a much broader physiological function for these receptors. T2Rs have been implicated in bronchodilation and in vasoconstriction. Quinine is an antimalarial drug and is one of the most bitter tasting compounds known. It is a natural alkaloid with a quinoline ring and a bicyclic quinuclidine. Quinine is a known agonist for T2Rs whereas BCML (Nα,Nα‐Bis(carboxymethyl)‐L‐lysine) acts as an inverse agonist. Since Rac1 is activated via various receptors like tyrosine kinase (RTKs), integrins and GPCRs; we have investigated the potential role of T2R4 in regulating Rac1 activity. In this study, HEK293T cells stably expressing T2R4/Gα 16/44 were transiently transfected with HA‐Rac1 followed by treatment with Quinine or Quinine plus BCML for 15 min. After incubation, active Rac1 was pulled‐down from cell lysate using GST‐PAK1 and anti‐Rac1 monoclonal antibody was used in Western blots to quantify amount of active Rac1. The results demonstrated that Quinine treatment resulted in significant (p<0.001) reduction in the amount of active Rac1 whereas in the presence of BCML, Quinine failed to cause any significant change in the amount of active Rac1 when compared to untreated cells. This study is the first to show inhibitory downstream action of a T2R agonist on Rac1 function and further investigation will help in better understanding the extra‐oral physiological roles of T2Rs. Support or Funding Information This work is supported by a grant from Research Manitoba and the College of Dentistry.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".