The Role of Individual Residues in the N-Terminus of Arrestin-1 in Rhodopsin Binding

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(2), С. 715 - 715

Опубликована: Янв. 16, 2025

Sequences and three-dimensional structures of the four vertebrate arrestins are very similar, yet in sharp contrast to other subtypes, arrestin-1 demonstrates exquisite selectivity for active phosphorylated form its cognate receptor, rhodopsin. The N-terminus participates receptor binding serves as anchor C-terminus, release which facilitates arrestin transition into a receptor-binding state. We tested effects substitutions fourteen residues on unphosphorylated light-activated rhodopsin wild-type protein enhanced mutant with C-terminal deletion that higher both functional forms Profound mutations identified lysine-15 main phosphate sensor phenylalanine-13 key C-terminus. These conserved all subtypes. Substitutions five reduced rhodopsin, indicating participate fine-tuning binding. Differential numerous an suggest these two proteins bind differently.

Язык: Английский

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Attributes novel drug candidate: Constitutive GPCR signal bias mediated by purinergic receptors

Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown, С. 108802 - 108802

Опубликована: Янв. 1, 2025

Язык: Английский

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Regulation of GLP-1 and Glucagon Receptor Function by β-Arrestins in Metabolically Important Cell Types

Biochemistry, Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) are polypeptides derived from a common precursor (preproglucagon) that modulates the activity of numerous cell types involved in regulating glucose energy homeostasis. GLP-1 GCG exert their biological functions via binding to specific G protein-coupled receptors (GLP-1Rs GCGRs). Ligand-activated GLP-1Rs GCGRs preferentially activate heterotrimeric protein Gs, resulting increased cytosolic cAMP levels. However, activation two also leads recruitment β-arrestin-1 -2 (βarr1 βarr2, respectively) intracellular surface receptor proteins. The β-arrestins activated contributes termination receptor-stimulated coupling. In addition, receptor-β-arrestin complexes can act as signaling nodes own right by modulating many pathways. this Review, we will discuss roles βarr1 βarr2 key metabolic mediated GCGRs. During past decade, GLP-1R agonists have emerged highly efficacious antidiabetic antiobesity drugs. Moreover, dual stimulate both predicted offer additional therapeutic benefits compared agonist monotherapy. We summarize try synthesize series studies suggesting development protein-biased and/or GCGR agonists, which do not lead β-arrestins, may even more agents.

Язык: Английский

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The complexity of G protein‐coupled receptor (GPCR) modulation and signalling

British Journal of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Май 9, 2025

Язык: Английский

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Deciphering complexity of GPCR signaling and modulation: implications and perspectives for drug discovery

Clinical Science, Год журнала: 2025, Номер 139(10), С. 463 - 477

Опубликована: Май 1, 2025

G protein-coupled receptors (GPCRs) are central to pathophysiological processes and remain prominent targets in drug discovery. Recent advances understanding GPCR signaling modulation, such as biased agonism, dual non-canonical protein signaling, have expanded the therapeutic landscape of these receptors. These understandings led (and leading further) innovative approaches that broaden GPCRs targets, going after better efficacy minimizing adverse effects. However, tachyphylaxis, a rapid decrease receptor responsiveness repeated stimulation, presents significant challenge chronic treatment context. findings from our group revealed tachyphylaxis angiotensin type 1 (AT1) is primarily governed by ligand's dissociation rate (koff), i.e. high residence time, rather than β-arrestin-mediated desensitization, could be expected. This suggests internalized AT1 active when bound ligands with favoring sustained endosomes. Importantly, concept time sheds new light on intracellular phenomena underscores value modulating activity, including development novel cell-permeant antagonists. review discusses critical pharmacological parameters for discovery focused agonists, (i) activation preferential pathways (biased agonism), (ii) internalization/recycling rates, (iii) tachyphylaxis/desensitization, (iv) allosteric modulators, (v) its blockade, emphasizing need strategies extend beyond conventional GPCRs' functional assays. Additionally, this highlights how advancements high-resolution imaging, bioluminescence resonance energy transfer-based biosensors, computational modeling crucial elucidating complex behaviors, particularly mechanisms like interplay compartment-specific signaling. not only pave way therapies strategically leverage or mitigate sustain responsiveness, but enable design drugs targeting strategy enhance minimize insights underscore importance integrating diverse refine GPCR-targeted address unmet medical needs, conditions where activity critical.

Язык: Английский

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Biodiversity2Drugs—Renaissance of exploring nature‐derived peptides for GPCR ligand discovery

British Journal of Pharmacology, Год журнала: 2025, Номер unknown

Опубликована: Май 29, 2025

Язык: Английский

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