A lipidated peptide derived from the C-terminal tail of the vasopressin 2 receptor shows promise as a new β-arrestin inhibitor
Bibliographic record
Abstract
β-arrestins play pivotal roles in seven transmembrane receptor (7TMR) signalling and trafficking. To study their functional role in regulating specific receptor systems, current research relies mainly on genetic tools, as few pharmacological options are available. To address this issue, we designed and synthesised a novel lipidated phosphomimetic peptide inhibitor targeting β-arrestins, called ARIP, which was developed based on the C-terminal tail (A343-S371) of the vasopressin V2 receptor. As the V2R sequence has been shown to bind β-arrestins with high affinity, we added an N-terminal palmitate residue to allow membrane tethering and cell entry. Here, using BRET 2 -based biosensors, we demonstrated the ability of ARIP to inhibit agonist-induced β-arrestin recruitment on a series of 7TMRs that includes both stable and transient β-arrestin binders, with efficiencies that dependent on receptor type. In addition, we showed that ARIP was unable to recruit β-arrestins to the cell membrane by itself, and that it did not interfere with G protein signalling. Molecular modelling studies also revealed that ARIP binds β-arrestins as does V2Rpp, the phosphorylated peptide derived from V2R, and that replacing the p-Ser and p-Thr residues of V2Rpp with Glu residues does not alter ARIP’s inhibitory activity on β-arrestin recruitment. Importantly, ARIP exerted an opioid-sparing effect in vivo , as intrathecal injection of ARIP potentiated morphine’s analgesic effect in the tail-flick test, consistent with previous findings of genetic inhibition of β-arrestins. ARIP therefore represents a promising pharmacological tool for investigating the fine-tuning roles of β-arrestins in 7TMR-driven pathophysiological processes. • ARIP is a membrane-tethered lipopeptide derived from the C-terminal tail of V2R • ARIP inhibits β-arrestin recruitment to multiple G protein-coupled receptors • ARIP does not recruit β-arrestins on its own nor interfere with G protein signalling • Intrathecal administration of ARIP potentiates morphine-induced analgesia in rats • ARIP is a promising new pharmacological tool to understand the contributions of pharmacological tool to understand the β-arrestins
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| 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 | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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 teacher head, 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".