Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates. We compared the roles of arrestin-3 conformational equilibrium and Lys-295 in GPCR binding and JNK3 activation. Several mutants with enhanced ability to bind GPCRs showed much lower activity towards JNK3, whereas a mutant that does not bind GPCRs was more active. The subcellular distribution of mutants did not correlate with GPCR recruitment or JNK3 activation. Charge neutralization and reversal mutations of Lys-295 differentially affected receptor binding on different backgrounds but had virtually no effect on JNK3 activation. Thus, GPCR binding and arrestin-3-assisted JNK3 activation have distinct structural requirements, suggesting that facilitation of JNK3 activation is the function of arrestin-3 that is not bound to a GPCR.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10296906 | PMC |
| http://dx.doi.org/10.3390/cells12121563 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Targeting JNK3 for Alzheimer's disease: Design and synthesis of novel inhibitors with aryl group diversity utilizing wide pocket.
Eur J Med Chem
January 2025
Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 15588, Republic of Korea. Electronic address:
JNK3, a brain-specific stress-activated protein kinase, plays a critical role in Alzheimer's disease pathogenesis through phosphorylation of Tau and APP. This study aimed to develop selective JNK3 inhibitors based on a pyrazole scaffold, focusing on (E)-1-(2-aminopyrimidin-4-yl)-4-styryl-1H-pyrazole-3-carboxamide derivatives. Through systematic structural modifications and extensive SAR analysis, we identified compounds 24a and 26a as highly potent JNK3 inhibitors, with IC values of 12 and 19 nM, respectively.
View Article and Find Full Text PDFA focus on c-Jun-N-terminal kinase signaling in sepsis-associated multiple organ dysfunction: Mechanisms and therapeutic strategies.
Int Immunopharmacol
December 2024
Laboratory of Neuroendocrinology, Department of Pharmacology, Central University of Punjab, Ghudda, Bathinda, India. Electronic address:
Sepsis is a life-threatening condition characterized by a widespread inflammatory response to infection, inevitably leading to multiple organ dysfunctions. Extensive research, both in vivo and in vitro, has revealed key factors contributing to sepsis, such as apoptosis, inflammation, cytokine release, oxidative stress, and systemic stress. The changes observed during sepsis-induced conditions are mainly attributed to altered signal transduction pathways, which play a critical role in cell proliferation, migration, and apoptosis.
View Article and Find Full Text PDFAnticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety.
Bioorg Chem
December 2024
Pharmaceutical Chemistry Department, Collage of Pharmaceutical Science and Drug Manufacturing, Misr University for Science and Technology, P.O. 77, 6th of October City, Giza, Egypt.
In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers.
View Article and Find Full Text PDFSelective Covalent Inhibiting JNK3 by Small Molecules for Parkinson's Diseases.
Angew Chem Int Ed Engl
December 2024
State Key Laboratory of Biotherapy and Cancer Center, Innovation Center of Nursing Research, West China Hospital, Sichuan University, No. 17, Section 3, Renmin South Road, 610041, Chengdu, China.
c-Jun N-terminal kinases (JNKs) including JNK1/2/3 are key members of mitogen-activated protein kinase family. Wherein JNK3 is specifically expressed in brain and emerges as therapeutic target, especially for neurodegenerative diseases. However, developing JNK3 selective inhibitors as chemical probes to investigate its therapeutic potential in diseases remains challenging.
View Article and Find Full Text PDFThe selective disruption of the JNK2/Syntaxin-1A interaction by JGRi1 protects against NMDA-evoked toxicity in SH-SY5Y cells.
Neurochem Int
October 2024
EBRI Rita Levi-Montalcini Foundation, Rome, Italy; Department of Neuro-Rehabilitation Sciences, Casa di Cura Igea, Milan, Italy. Electronic address:
N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion-channel receptors, specifically activated by glutamate, that permit the activation of specific intracellular calcium-dependent pathways. Aberrant NMDA receptor activation leads to a condition known as excitotoxicity, in which excessive calcium inflow induces apoptotic pathways. To date, memantine is the only NMDA receptor antagonist authorized in clinical practice, hence, a better understanding of the NMDA cascade represents a need to discover novel pharmacological targets.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!