Cryo-EM structure of the bicarbonate receptor GPR30 DOI Open Access
Shota Kaneda,

Airi Jo-Watanabe,

Hiroaki Akasaka

et al.

Published: July 26, 2024

G-protein-coupled receptor 30 (GPR30) is a bicarbonate that plays vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with ions remain elusive. There no consensus on drug targets GPR30, difficulty pharmacological analysis has limited biological discovery researches GPR30. Here, we present cryo-electron microscopy structure of human presence at 3.2 Å resolution. Our reveals unique pockets critical residues for binding activation. Functional assays demonstrate mutations these impair bicarbonate-induced activation, underscoring their importance function. This study also provides insights into G-protein coupling, highlighting structural divergence between other GPCRs. findings not only advance understanding homeostasis but pave way development high-affinity drugs targeting therapeutic interventions diseases associated acid-base imbalance.

Language: Английский

Compartment-Specific Activation of the Proton-Sensor GPR65 is Uncoupled from Receptor Trafficking DOI Creative Commons
Loyda M. Morales Rodríguez, Stephanie E. Crilly, Jacob B. Rowe

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 21, 2023

ABSTRACT The canonical view of G protein-coupled receptor (GPCR) function is that trafficking tightly coupled to signaling. GPCRs remain on the plasma membrane (PM) at cell surface until they are activated, after which desensitized and internalized into endosomal compartments. This presents an interesting context for proton-sensing because more likely be activated in acidic compartments than PM. Here we show prototypical proton-sensor GPR65 fully uncoupled from signaling, unlike other known mammalian GPCRs. localized early late endosomes, where signal steady state, irrespective extracellular pH. Acidic environments stimulated signaling PM a dose-dependent manner, although was still required full response. Receptor mutants were incapable activating cAMP trafficked normally, internalized, Our results constitutively active suggest model changes pH reprograms spatial pattern biases location surface.

Language: Английский

Citations

1

Advances in GPCRs: structure, mechanisms, disease, and pharmacology DOI
Zeyu Cai, Wei Kong

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 326(5), P. C1291 - C1292

Published: March 25, 2024

Language: Английский

Citations

0

Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene DOI Open Access

Olivia Garnier,

Florian Jeanneret,

Aude Durand

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 22, 2024

Abstract Cancer and inflammation are associated with vascular diseases that affect endothelial cells (ECs) alter gene expression. We aimed at understanding whether the site Y 685 in cytoplasmic domain of VE-cadherin triggers epigenetic programming vivo . Using our knock-in mice carrying F mutation, RNA sequencing from lung ECs identified 884 differentially expressed genes (DEG) involved processes such as cell-cell adhesion, development, angiogenesis. The 30 DEGs include 22 down-regulated (genes encoding cell signalling enzymes, anion transport lipid metabolism) 8 up-regulated genes, including endothelial-specific S1PR1. Analysis VEGF/VEGFR2 signaling pathway shows a significant decrease expression pY 1173 VEGFR2 whereas VEGF remains constant, this was consistent impaired migration, proliferation protrusive properties vitro Co-immunoprecipitation experiments showed c-Src F-VE-cadherin association which enhanced KI compared to WT, resulting increased phosphorylation 731 As consequence, its partner β-catenin translocates nucleus. CHIPS assay FOXF1 binds s1pr1 promoter, leading In vivo, vasculature, process vessel wall thickness reduced fibrosis. Overall, findings provide novel transcriptomic profile triggered by for potential insights into therapeutic targets envisage normalisation tumor vasculature.

Language: Английский

Citations

0

Cryo-EM structure of the bicarbonate receptor GPR30 DOI Creative Commons
Shota Kaneda, Airi Jo‐Watanabe, Hiroaki Akasaka

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 19, 2024

Abstract G-protein-coupled receptor 30 (GPR30) is a bicarbonate that plays vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with ions remain elusive. There no consensus on drug targets GPR30, difficulty pharmacological analysis has limited biological discovery researches GPR30. Here, we present cryo-electron microscopy structure of human presence at 3.2 Å resolution. Our reveals unique pockets critical residues for binding activation. Functional assays demonstrate mutations these impair bicarbonate-induced activation, underscoring their importance function. This study also provides insights into G-protein coupling, highlighting structural divergence between other GPCRs. findings not only advance understanding homeostasis but pave way development high-affinity drugs targeting therapeutic interventions diseases associated acid-base imbalance.

Language: Английский

Citations

0

Cryo-EM structure of the bicarbonate receptor GPR30 DOI Open Access
Shota Kaneda,

Airi Jo-Watanabe,

Hiroaki Akasaka

et al.

Published: July 26, 2024

G-protein-coupled receptor 30 (GPR30) is a bicarbonate that plays vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with ions remain elusive. There no consensus on drug targets GPR30, difficulty pharmacological analysis has limited biological discovery researches GPR30. Here, we present cryo-electron microscopy structure of human presence at 3.2 Å resolution. Our reveals unique pockets critical residues for binding activation. Functional assays demonstrate mutations these impair bicarbonate-induced activation, underscoring their importance function. This study also provides insights into G-protein coupling, highlighting structural divergence between other GPCRs. findings not only advance understanding homeostasis but pave way development high-affinity drugs targeting therapeutic interventions diseases associated acid-base imbalance.

Language: Английский

Citations

0