Hypothalamic opsin 3 suppresses MC4R signaling and potentiates Kir7.1 to promote food consumption

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 14, 2025

Mammalian opsin 3 (OPN3) is a member of the family G-protein-coupled receptors with ambiguous light sensitivity. OPN3 was first identified in brain (and named encephalopsin) and subsequently found to be expressed other tissues. In adipocytes, necessary for responses that modulate lipolysis glucose uptake, while human skin melanocytes regulates pigmentation light-independent manner. Despite its initial discovery brain, functional mechanisms remain elusive. Here, we investigated molecular mechanism function paraventricular nucleus (PVN) hypothalamus. We show Opn3 coexpressed melanocortin 4 receptor (Mc4r) population PVN neurons, where it negatively MC4R-mediated cAMP signaling specific Gαi/o-dependent Under baseline conditions, via Gαi/o potentiates activity inward rectifying Kir7.1 channel, previously shown closed response agonist-mediated activation MC4R Gαs-independent mice, Mc4r-expressing neurons food consumption. Our results reveal mechanistic insight into hypothalamus, uncovering unique by which functions potentiate regulate signaling, thereby promoting intake.

Language: Английский

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Protein kinase A and local signaling in cancer

Biochemical Journal, Journal Year: 2024, Volume and Issue: 481(22), P. 1659 - 1677

Published: Nov. 14, 2024

Protein kinase A (PKA) is a basophilic implicated in the modulation of many cell-signaling and physiological processes. PKA also contributes to cancer-relevant events such as growth factor action, cell cycle control, migration tumor metabolism. Germline somatic mutations PKA, gene amplifications, chromosome rearrangements that encode fusions, are linked growing number malignant neoplasms. Mislocalization by exclusion from A-Kinase Anchoring (AKAP) signaling islands further underlies cancer progression. This article highlights influence AKAP local action selected hallmarks cancer. We feature utility inhibitor drugs frontline future anti-cancer therapies.

Language: Английский

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Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(8)

Published: Feb. 18, 2025

G protein–coupled receptors (GPCRs) modulate various physiological functions by rewiring cellular gene expression in response to extracellular signals. Control of GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount regulation that takes place translationally. Hence, little is known about nature and mechanisms gene-specific posttranscriptional downstream receptor activation. Here, we apply unbiased multiomics approach delineate translational regulatory program initiated prototypical beta2-adrenergic (β2-AR) provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), identify nearly 120 targets adrenergic activity for which regulated level translation. We next show all changes induced selectively endosomal β2-ARs report this proceeds through activation mammalian target rapamycin (mTOR) pathway. Specifically, within set GPCR targets, find significant enrichment genes with 5’ terminal oligopyrimidine (TOP) motifs, a class classically be translationally mTOR. then demonstrate required mTOR subsequent mTOR-dependent TOP mRNA This site-selective crosstalk between pathways observed multiple cell models native β2-ARs, across range endogenous synthetic agonists, other intracellular activity. Together, comprehensive analysis drug-induced establishes critical role location-biased signaling fine-tuning protein landscape.

Language: Английский

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Kanglexin attenuates spinal cord injury by modulating pyroptosis and polarization via the PKA/NF-κB signaling pathway

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 153, P. 114401 - 114401

Published: March 17, 2025

Language: Английский

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Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2+

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 9, 2025

Abstract ANO1 plays a crucial role in determining numerous physiological functions, including epithelial secretion, yet its regulatory mechanisms remain incompletely understood. Here, we describe fundamental dynamic regulation of surface expression and Ca 2+ -dependent gating via the cAMP/PKA pathway at STIM1 ER/PM junctions. At these junctions, assembles AC-AKAP-PKA complexes, while E-Syt1 mediates formation ANO1-VAPA-IRBIT-E-Syt1-AC8-AKAP5-PKA complex, that phosphorylates S673, increasing affinity. Within cAMP pathways act synergistically to enhance function. By contrast, E-Syt2 dissociates ANO1-VAPA interaction, forming ANO1-IRBIT-E-Syt2-AC6-AKAP11-PKA complex S221, which markedly reduces The effects E-Syts are primarily mediated by their reciprocal junctional PI(4)P, PI(4,5)P 2 PtdSer. Accordingly, IRBIT deletion mice impairs receptor-stimulated activation fluid secretion. These findings should have broad implications for roles functions across various tissues.

Language: Английский

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Autophagosomes anchor an AKAP11-dependent regulatory checkpoint that shapes neuronal PKA signaling

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Abstract Protein Kinase A (PKA) is regulated spatially and temporally via scaffolding of its catalytic (Cα) regulatory (RI/RII) subunits by the A-kinase-anchoring proteins (AKAP). By binding to an AKAP11 scaffold, PKA engages in poorly understood interactions with autophagy, a key degradation pathway for neuronal cell homeostasis. Mutations promote schizophrenia bipolar disorders (SZ-BP) through unknown mechanisms. Here, proteomic-based analyses immunopurified lysosomes, we identify Cα-RIα-AKAP11 holocomplex as prominent autophagy-associated protein-kinase complex. scaffolds Cα-RIα interaction autophagic machinery LC3-interacting region (LIR), enabling both regulation upstream signals, autophagy-dependent degradation. We Ser83 on RIα linker-hinge AKAP11-dependent phospho-residue that modulates RIα-Cα autophagosome cAMP-induced activation. Decoupling AKAP11-PKA from autophagy alters downstream phosphorylation events, supporting checkpoint signaling. Ablating induced pluripotent stem cell-derived neurons reveals dysregulation multiple pathways Thus, platform signaling, providing possible mechanistic link SZ/BP pathophysiology.

Language: Английский

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A signal transduction blind spot: the function of adenylyl cyclase transmembrane domains

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

Signal transduction of external primary signals into intracellular elevations the second messenger cyclic AMP is an ancient and universal regulatory mechanism in biology. In mammals, 9 10 adenylyl cyclases (ACs) share a common topology that includes large transmembrane (TM) domain assembled from two clusters six helices. This accounts for ~ 35% coding sequence but, remarkably, its function still open question. this viewpoint, we consider how first AC sequences spurred ideas purpose TM domains, including voltage‐sensing transporter functions. original conceptions signalling, ACs were put forward as potential receptors, discuss emerging evidence support function. We also growing cyclase helical bundles help to organise multiprotein signalling complexes by engaging interactions with other membrane‐embedded proteins. Cyclase regions are more diverse between isoforms than catalytic domain—we conclude considering might be exploited therapeutic strategies targeting specific isoforms.

Language: Английский

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A bio. tools collection of online resources for GPCR research

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

G protein-coupled receptors are highly complex signal transduction proteins with many potential biomedical applications. Researchers from different fields work together to improve mechanistic understanding of GPCR function and transfer that knowledge in order advance therapeutic options. Due the interdisciplinary nature research, databases web tools types levels information being developed support scientists sharing analysing data. Here, we aim give an overview freely available online chemoinformatics bioinformatics resources specifically designed aid research. We compiled a dedicated domain on ELIXIR's bio. portal as continuously updatable repository GPCR-related (https://bio.tools/t?domain=gpcr). This provides up-to-date tools, rather than static list representing only snapshot time. Furthermore, some recommendations for developing using scientific briefly describe selected web-based

Language: Английский

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The evolution of AKAPs and emergence of PKA isotype selective anchoring determinants

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108480 - 108480

Published: April 1, 2025

Cyclic AMP is a versatile signaling molecule utilized throughout the eukaryotic domain. A frequent use to activate protein kinase (PKA), serine/threonine that drives many physiological responses. Spatiotemporal organization of PKA occurs though association with A-kinase anchoring proteins (AKAPs). Sequence alignments and phylogenetic analyses trace evolution regulatory (R) catalytic (C) subunits, AKAPs from emergence metazoans. preferentially associate type I (RI), or II (RII) subunits diverged at advent vertebrate clade. Type including smAKAP contain an FA motif positions 1 2 their amphipathic binding helices. Fluorescence recovery after photobleaching (FRAP) measurements indicate associates RI (T 1/2. 4.37 ± 1.2 sec; n=3) as compared RII 2.19 0.5 n=3). Parallel studies measured AKAP79 half times 8.74 0.3 sec (n=3) for 14.42 2.1 respectively. Introduction AF motifs either ends helix biases full length toward reduce corticosterone release adrenal cells by 61.5 0.8 % (n=3). Conversely, substitution YA beginning pair leucine's abrogates anchoring. Thus, have evolved base metazoan clade into specialized proteins.

Language: Английский

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Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera

FEBS Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 13, 2024

Cyclic AMP (cAMP) has a crucial role in many vital cellular processes and there been much effort expended the discovery of inhibitors against enzyme superfamily that degrades this second messenger, namely phosphodiesterases (PDEs). The journey competitive PDE to clinic hampered by side effects profiles have resulted from lack selectivity for subfamilies individual isoforms because high conservation catalytic site sequences structures. Here we introduce proteolysis targeting chimera (PROTAC) can specifically target small subset PDE4 family send degradation at proteasome recruiting ubiquitin E3 ligase into proximity with PDE. We constructed our PROTAC (KTX207) using previously characterized inhibitor, show evolution compound improves selectivity, potency enables long‐lasting effect even after is removed cells short treatment duration. Functionally, KTX207 more effective increasing cAMP, 100 times anti‐inflammatory, significantly better reducing growth cancer cell models than inhibitor alone. Our study highlights advantages targeted versus active‐site occupancy inhibition discusses potential novel pharmacological approach improve safety profile future.

Language: Английский

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