Identification of key regions mediating human melatonin type 1 receptor biased signaling revealed by natural variants
Bibliographic record
Abstract
Background Melatonin is a circulating neurohormone mainly released from the pineal gland in a circadian manner regulating many physiological functions, such as glycemia homeostasis. A misregulation of the glycemia could lead to Type 2 Diabetes (T2D). Recently, a genetic variant (rs2119882) found on melatonin type 1 receptor (MT1) promoter has been associated to higher risks to develop T2D. Hypothesis Variants on the MT1 coding region could modify receptor signalling and consequently modulate incidence to develop T2D. Methods we performed a genome‐wide association studies with both normoglycemic individuals and T2D patients and 32 non synonymous polymorphisms of MT1 were identified. Our primary aim was to functionally characterize these variants to further verify if there is an association between specific impaired signaling pathways and higher risks to develop T2D. Affinity for melatonin (Kd) and cell surface expression of variants were measured using 125 I‐melatonin binding assays and enzyme‐linked immunosorbent assay (ELISA) respectively to be sure that all receptors were expressed at the cell surface. Melatonin dose‐response curves were performed at equivalent cell surface expression to determine MT1s efficacy and potency to activate each G protein using a bioluminescence resonance energy transfer (BRET) assay monitoring proximity between G alpha and G gamma proteins as activation indicator. Finally, b‐arrestin 2 recruitment to cytoplasmic membrane upon MT1s stimulated with melatonin was measured by monitoring BRET between RlucII‐fused b‐arrestin and the cytoplasmic membrane targeted sensor (rGFP‐fused to CAAX box of KRas). Results Results obtained by the functional characterization indicate several types of signaling signatures. Indeed, some mutations show a biased signaling between G protein activation and b‐arrestin recruitment, while others show G protein isoform selectivity. Conclusion Association studies between patients having MT1 mutations and these signaling signatures will help us to understand in a better way the relationship between melatonin and insulin and represent an opportunity to identify new potential genetic markers of higher risks to develop T2D. Support or Funding Information This work was supported by a grant from CIHR to MB, from FRM, ANR and Université Paris 5 Descartes to RJ and from NIH, NSF and DARPA to OL. PhD student fellowship from Université de Montréal to AH, postdoctoral fellowships from CIHR and from Diabetes Canada to BP and from FRM to AK also funded this work. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.000 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".