Function of gastrin-releasing peptide receptors in ocular itch transmission in the mouse trigeminal sensory system DOI Creative Commons
Keiko Takanami,

M. KUROIWA,

Ren Ishikawa

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Nov. 30, 2023

The prevalence of allergic conjunctivitis in itchy eyes has increased constantly worldwide owing to environmental pollution. Currently, anti-allergic and antihistaminic eye drops are used; however, there many unknown aspects about the neural circuits that transmit eyes. We focused on gastrin-releasing peptide (GRP) GRP receptor (GRPR), which reportedly involved itch transmission spinal somatosensory system, determine whether system is neurotransmission trigeminal sensory system. First, instillation mediators, such as histamine (His) non-histaminergic mediator chloroquine (CQ), exhibited concentration-dependent high levels scratching behavior, with a significant sex differences observed case His. Histological analysis revealed His CQ significantly activity GRPR-expressing neurons caudal part nucleus medulla oblongata GRPR transgenic mice. administered antagonist or bombesin-saporin ablate neurons, followed by instillation, decrease CQ-induced eye-scratching behavior toxin experiments. Intracisternal administration neuromedin C (NMC), agonist, resulted dose-dependent excessive facial despite absence an stimulus face. To our knowledge, this first study demonstrate were transmitted centrally via NMC evoked itching.

Language: Английский

Radiopharmaceuticals and their applications in medicine DOI Creative Commons
Siqi Zhang, Xingkai Wang, Xin Gao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 2, 2025

Abstract Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for diagnosis and treatment multiple diseases. Radiopharmaceutical therapy, which directly causes systematic irreparable damage cells, has attracted increasing attention in refractory diseases that are not sensitive current therapies. As Food Drug Administration (FDA) approvals [ 177 Lu]Lu-DOTA-TATE, Lu]Lu-PSMA-617 their complementary diagnostic agents, namely, 68 Ga]Ga-DOTA-TATE Ga]Ga-PSMA-11, radiopharmaceutical-based theranostics (radiotheranostics) being increasingly implemented clinical practice oncology, lead a new era radiopharmaceuticals. The generation radiopharmaceuticals utilizes targeting vector achieve accurate avoid off-target deposition, making it possible improve efficiency biosafety tumour therapy. Numerous studies have focused on developing novel broader range disease targets, demonstrating remarkable vivo performance. These include high tumor uptake, prolonged retention time, favorable pharmacokinetic properties align with standards. While radiotheranostics been widely applied applications now expanding neurodegenerative diseases, cardiovascular inflammation. Furthermore, radiotheranostic-empowered precision medicine is revolutionizing cancer paradigm. Diagnostic play pivotal role patient stratification planning, leading improved therapeutic outcomes radionuclide This review offers comprehensive overview evolution radiopharmaceuticals, including both FDA-approved clinically investigated explores mechanisms cell death induced by It emphasizes significance future prospects theranostic-based advancing medicine.

Language: Английский

Citations

15
Proton perception and activation of a proton-sensing GPCR DOI

Li-Nan Chen,

Hui Zhou, Kun Xi

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

1
Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer DOI Creative Commons
Honghu Zhang, Lin Qi, Yi Cai

et al.

Annals of Medicine, Journal Year: 2024, Volume and Issue: 56(1)

Published: March 5, 2024

This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in diagnosis and treatment prostate cancer. Additionally, study investigates role GRPR prognostic assessment for individuals afflicted with

Language: Английский

Citations

8
Cryo-EM Structures and AlphaFold3 Models of Histamine Receptors Reveal Diverse Ligand Binding and G Protein Bias DOI Creative Commons
Anqi Chen, Changwei Su, Zhe Zhang

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 292 - 292

Published: Feb. 21, 2025

Background: The four subtypes of G protein-coupled receptors (GPCRs) regulated by histamine play critical roles in various physiological and pathological processes, such as allergy, gastric acid secretion, cognitive sleep disorders, inflammation. Previous experimental structures (HRs) with agonists antagonists exhibited multiple conformations for the ligands protein binding. However, structural basis HR regulation signaling remains elusive. Methods: We determined cryo-electron microscopy (cryo-EM) structure H4R-histamine-Gi complex at 2.9 Å resolution, predicted models all HRs ligand-free apo subtype binding states using AlphaFold3 (AF3). Results: By comparing our H4R computational AF3 models, we elucidated distinct modes interfaces, proposed essential Y6.51 Q7.42 receptor activation intracellular loop 2 (ICL2) bias. Conclusions: Our findings deciphered molecular mechanisms underlying different HRs, from extracellular ligand-binding pockets transmembrane motifs to coupling interfaces. These insights are expected facilitate selective drug discovery targeting diverse therapeutic purposes.

Language: Английский

Citations

1
GRP/GRPR enhances alcohol-associated liver injury through the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent ROS pathway DOI
Hai-Di Li, Xin Chen, Jiejie Xu

et al.

Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 392 - 408

Published: July 5, 2023

Background and Aims: The common characteristics of alcohol-associated liver injury (ALI) include abnormal function, infiltration inflammatory cells, generation oxidative stress. gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, (GRP). GRP/GRPR appears to induce the production cytokines in immune cells promotes neutrophil migration. However, effects ALI are unknown. Approach Results: We found high GRPR expression patients with steatohepatitis increased pro-GRP levels peripheral blood mononuclear these compared that control. Increased GRP may be associated histone H3 lysine 27 acetylation induced alcohol, which then binding. Grpr -/- flox/flox LysM Cre mice alleviated ethanol-induced relieved steatosis, lower serum alanine aminotransferase, aspartate triglycerides, malondialdehyde, superoxide dismutase levels, reduced influx, decreased release chemokines. Conversely, overexpression showed opposite effects. pro-inflammatory stress roles might dependent on IRF1-mediated Caspase-1 inflammasome NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified therapeutic preventive RH-1402, a novel antagonist, for ALI. Conclusions: A knockout or antagonist during excess alcohol intake could have anti-inflammatory antioxidative roles, as well provide platform modification-based therapy

Language: Английский

Citations

14
IL-22 in Atopic Dermatitis DOI Creative Commons
Julia Laska, Maciej Tota,

Julia Łacwik

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(16), P. 1398 - 1398

Published: Aug. 22, 2024

Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin condition characterized by multifaceted pathophysiology that gives rise to diverse clinical manifestations. The management of AD remains challenging due the suboptimal efficacy existing treatment options. Nonetheless, recent progress in elucidating underlying mechanisms disease has facilitated identification new potential therapeutic targets promising drug candidates. In this review, we summarize newest data, considering multiple connections between IL-22 AD. presence circulating been found correlate with severity identified as critical factor driving response associated condition. Elevated levels patients are correlated increased proliferation keratinocytes, alterations microbiota, impaired epidermal barrier function. Collectively, these factors contribute manifestation characteristic symptoms observed

Language: Английский

Citations

6
Novel insight on GRP/GRPR axis in diseases DOI Open Access

Haolu Sun,

Qiuying Ma,

He-ge Bian

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114497 - 114497

Published: March 16, 2023

The gastrin-releasing peptide receptor (GRPR), a member of the G protein-coupled receptors (GPCRs), binds to ligands such as (GRP) and plays variety biological roles. GRP/GRPR signalling is involved in pathophysiological processes many diseases, including inflammatory cardiovascular neurological various cancers. In immune system, unique function neutrophil chemotaxis suggests that GRPR can be directly stimulated through GRP-mediated neutrophils activate selective pathways, PI3K, PKC, MAPK, participate occurrence development inflammation-related diseases. GRP increases intercellular adhesion molecule 1 (ICAM-1) induces vascular cell molecule-1 (VCAM-1). activates ERK1/2, AKT, leading myocardial infarction. Central nervous system signal transduction mediated by axis vital role emotional responses, social interaction, memory. elevated cancers, lung, cervical, colorectal, renal cell, head neck squamous carcinomas. mitogen tumour lines. Its precursor, pro-gastrin-releasing (ProGRP), may play an important emerging marker early diagnosis. GPCRs serve therapeutic targets for drug development, but their each disease remains unclear, involvement progression has not been well explored or summarised. This review lays out above mentioned based on previous research conclusions. potential target treating multiple study this particularly important.

Language: Английский

Citations

12
Structure-Function Analysis of Plant G-protein Regulatory Mechanisms Identifies Key Gα-RGS Protein Interactions DOI Creative Commons

María Daniela Torres-Rodríguez,

Soon Goo Lee,

Swarup Roy Choudhury

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(5), P. 107252 - 107252

Published: April 1, 2024

Heterotrimeric GTP-binding protein alpha subunit (Gα) and its cognate regulator of G-protein signaling (RGS) transduce signals in eukaryotes spanning protists, amoeba, animals, fungi, plants. The core catalytic mechanisms the GTPase activity Gα interaction interface with RGS for acceleration GTP hydrolysis seem to be conserved across these groups; however, gene is under low selective pressure plants, resulting frequent loss. Our current understanding structural basis Gα:RGS regulation plants has been shaped by Arabidopsis Gα, (AtGPA1), which a protein. To gain comprehensive this beyond Arabidopsis, we obtained x-ray crystal structures Oryza sativa no RGS, Selaginella moellendorffi lycophyte that sequence similarity AtGPA1 but an RGS. We show three-dimensional structure, protein-protein dynamic features are similar metazoan Gα. Molecular simulation Gα-RGS identifies contacts established specific residues switch regions GTP-bound crucial interaction, finds significant difference due amino acid substitutions. Together, our data provide valuable insights into regulatory plant G-proteins, do not support hypothesis adaptive co-evolution proteins

Language: Английский

Citations

4
Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3 DOI Creative Commons
Changyao Li, Youwei Xu, Wenxin Su

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114511 - 114511

Published: July 17, 2024

Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled that regulates energy homeostasis and insulin secretion. As a member of the bombesin (BnR) family, lack known endogenous ligands high-resolution structure has hindered understanding BRS3 signaling function. We present two cryogenic electron microscopy (cryo-EM) structures in complex with heterotrimeric

Language: Английский

Citations

3
Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif DOI Creative Commons
Kazutoshi Tani, Saori Maki-Yonekura,

Ryo Kanno

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Oct. 16, 2024

Abstract Endothelin type B receptor (ET R) plays a crucial role in regulating blood pressure and humoral homeostasis, making it an important therapeutic target for related diseases. ET R activation by the endogenous peptide hormones endothelin (ET)−1–3 stimulates several signaling pathways, including G s , i/o q/11 12/13 β-arrestin. Although conserved NPxxY motif transmembrane helix 7 (TM7) is during GPCR activation, possesses lesser known NPxxL motif. In this study, we present cryo-EM structure of R–G i complex, complemented MD simulations functional studies. These investigations reveal unusual movement TM7 to intracellular side essential roles diverse stabilizing active conformation organizing assembly binding pocket α5 protein. findings enhance our understanding interactions between GPCRs proteins, thereby advancing development strategies.

Language: Английский

Citations

3