Molecular Pharmacology最新文献

{"title":"GRK2 and GRK5-The 2 critical kinases in cardiac pathophysiology.","authors":"Rajika Roy, Walter J Koch","doi":"10.1016/j.molpha.2025.100095","DOIUrl":"10.1016/j.molpha.2025.100095","url":null,"abstract":"<p><p>G protein-coupled receptor kinases (GRKs) are a class of serine/threonine kinases that shut down active signaling mediated by agonist-bound G protein-coupled receptors. Of all the diseases that arise from dysfunctional G protein-coupled receptor-GRK interactions, this review will focus on the roles of the 2 most highly expressed GRKs in heart failure (HF)-GRK2 and GRK5. Both are upregulated in human and mouse HF heart samples. Because both GRK2 and GRK5 are expressed in all cardiac cell types-cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, and cardiomyocytes-it is essential to examine their role in these individual cell types for identifying specific cardiomyopathies and targeting them accordingly. Seminal work from our laboratory over the last 3 decades has uncovered multiple crucial aspects of GRK2- and GRK5-mediated interactions that lead to HF. Based on that, several GRK2 and GRK5 inhibitors have been identified/generated that have high potency and have been tested in multiple animal models of HF. One of the GRK2 inhibitors, paroxetine, has also been evaluated in 2 clinical trials. Similarly, potent GRK5 inhibitors have also been recently generated, and it remains to be seen how they affect cardiac structure and function in vivo. Lastly, assessing cell-specific fine differences in GRK2 and GRK5 inhibition will pave the way for identifying ideal patient cohorts for clinical trials in which selective GRK2 and GRK5 inhibitors can be evaluated as a new class of drugs for HF. SIGNIFICANCE STATEMENT: G protein-coupled receptor kinases 2 and 5 play a central role in heart failure (HF) onset and progression. They have critical significance in all cardiac cells, which contribute to the pathophysiology of HF, namely, cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. Dysfunction in their canonical G protein-coupled receptor-related function or noncanonical function must be sufficiently investigated and addressed to evaluate their inhibitors as a new class of drugs for HF.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100095"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors.","authors":"Lindsay P Cameron, Alaina M Jaster, Raul A Ramos, Elijah Z Ullman","doi":"10.1016/j.molpha.2025.100093","DOIUrl":"10.1016/j.molpha.2025.100093","url":null,"abstract":"<p><p>2,5-dimethoxy-4-iodoamphetamine (DOI) is a phenethylamine psychedelic with high affinity for 5-HT₂ receptors. In 2022 and 2023, the US Drug Enforcement Administration proposed to place DOI, along with a similar compound, 2,5-dimethoxy-4-chloroamphetamine, in Schedule I of the Controlled Substances Act based on their psychoactivity and alleged abuse potential. Here, we describe the history of DOI, its utility in preclinical neuroscience research, and how it has significantly advanced the study of 5-HT_2A and 5-HT_2C receptors. Finally, we suggest alternative compounds for studying 5-HT₂ receptors, should obtaining DOI for research become restricted. SIGNIFICANCE STATEMENT: 2,5-Dimethoxy-4-iodoamphetamine, the key pharmacological tool for studying 5-HT_2A receptor function and localization, has been used in more 1200 publications across 5 decades. This review covers its utility, research barriers if the Drug Enforcement Administration schedules it, and alternatives for continued investigation of serotonin receptors.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100093"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of small molecule ligands for GPR83 that modulate morphine antinociception and reward.","authors":"Ivone Gomes, Seshat M Mack, Roberto Sanchez, Anubhav Yadav, Mariana L Duarte, Lakshmi A Devi, Amanda K Fakira","doi":"10.1016/j.molpha.2025.100092","DOIUrl":"10.1016/j.molpha.2025.100092","url":null,"abstract":"<p><p>The opioid crisis showcases a need for novel therapeutic avenues to treat drug abuse. GPR83, a recently deorphanized G protein-coupled receptor shown to blunt morphine reward learning and regulate pain, is activated by the neuropeptide PEN and peptides derived from cholecystokinin. To identify small molecule ligands, we generated a homology model based on the crystal structure of related receptors and used virtual screening on a library of 7 million compounds. The top 50 hits were screened in a cell-based assay that identified 2 selective GPR83 agonists, CPD1 and CPD27, and 1 antagonist, CPD25. The model was validated by site-directed mutagenesis of GPR83 residues predicted to interact with these ligands; these mutations disrupted ligand binding to GPR83. The molecular pharmacological properties of these compounds were characterized, and their GPR83 specificity validated using knockdown cells generated using GPR83 short hair pin RNA. Peripheral antagonist (CPD25) administration to wild-type and GPR83 knockout mice blocked morphine conditioned place preference only in the wild-type mice supporting that CPD25-mediated blockade is through GPR83 antagonism. Interestingly, morphine antinociception was blunted by the GPR83 agonist (CPD1) and enhanced by CPD25 with a medium to large effect size estimate, demonstrating a role for GPR83 in regulating morphine analgesia. Taken together, we identified and validated small molecule modulators of GPR83 that could be used to probe its role in neuropsychiatric disorders. Our in vivo studies highlight GPR83 as a target that could be used to limit the addictive effects of opioids in the treatment of pain. SIGNIFICANCE STATEMENT: There is a need to identify targets that limit opioid abuse potential while maintaining the pain-relieving effects. This study identifies small molecule GPR83 ligands that block opioid reward learning while enhancing their pain-relieving effect.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100092"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism-based inactivation of human aldehyde oxidase by erlotinib: Mechanistic insights from structural analogs and molecular docking.","authors":"Jia Rong Kweh, Nicholas Kai Ming Ng, Le Min Ngoh, Cynthia Jing Yan Li, Bao Jie Tan, Wee Kiat Tan, Vijaya Saradhi Mettu, Karl Austin-Muttitt, Jonathan G L Mullins, Aik Jiang Lau","doi":"10.1016/j.molpha.2025.100097","DOIUrl":"10.1016/j.molpha.2025.100097","url":null,"abstract":"<p><p>Aldehyde oxidase (AOX1) is a cytosolic molybdo-flavoenzyme that metabolizes azaheterocyclic drugs. Erlotinib and gefitinib are azaheterocyclic drugs. We deployed structural analogs to investigate the molecular interaction between these drugs and AOX1. Erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib, but not gefitinib, O-desmethylgefitinib, or O-desmorpholinopropylgefitinib, decreased carbazeran 4-oxidation by liver cytosol (human, rat, and mouse) and human recombinant AOX1. Erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib exhibited time- and concentration-dependent inactivation with unbound inactivation potency (K_I,u) of 1.52, 4.41, and 1.67 μM, respectively. The inactivation was not reversed after dialysis, not protected by nucleophilic trapping agents or scavengers of reactive oxygen species, not affected by an oxidizing or reducing agent, but was attenuated by an alternative AOX1 substrate (O⁶-benzylguanine) and competitive AOX1 inhibitor (gefitinib). The terminal alkyne group of erlotinib was essential for AOX1 inactivation, as suggested by the findings for 3-vinylerlotinib (less potent inactivator) and tetrahydroerlotinib (no inactivation). Molecular docking results predicted covalent binding of erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib to the molybdenum cofactor. Adding a 4'-methyl group to erlotinib increased the inactivation potency but decreased inactivation efficiency, whereas blocking the C₂-position of erlotinib with a hydroxy group or a methyl group decreased inactivation potency and efficiency, suggesting that the C₂-position of erlotinib plays a role in AOX1 inactivation. In mice, erlotinib increased carbazeran (Aox substrate) and decreased 4-oxo-carbazeran (metabolite) levels in blood, liver, and kidneys. Overall, our study provides molecular insights into the mechanism-based inactivation of AOX1 by erlotinib, O-desmethylerlotinib, and O-didesmethylerlotinib and the irreversible AOX1 inactivation by erlotinib on the pharmacokinetics of AOX1-metabolized drugs. SIGNIFICANCE STATEMENT: This study shows that erlotinib and select metabolites are mechanism-based inactivators of AOX1, provides insights into the mechanism of the inactivation by deploying structural analogs and molecular docking, and demonstrates the in vivo impact on AOX1-mediated drug metabolism.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100097"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TRPV3 channels in bladder cancer cells stimulates ATP release.","authors":"Jonas Janenz, Andrea Leipe, Nicole Urban, Michael Schaefer, Kerstin Hill","doi":"10.1016/j.molpha.2025.100096","DOIUrl":"10.1016/j.molpha.2025.100096","url":null,"abstract":"<p><p>Transient receptor potential vanilloid 3 (TRPV3) is a thermosensitive Ca²⁺-permeable ion channel that plays essential roles in epithelial barrier function. Although its expression and function have been well characterized in the skin and, to a lesser extent, in the gastrointestinal tract, its role in the urinary bladder has remained unexplored. In this study, TRPV3 was identified in human bladder cancer cell lines, and its functional activation was demonstrated, using a novel small-molecule agonist activator of TRPV3 channel 1 (AV3-1), discovered through medium-throughput screening. AV3-1 activated mouse and human TRPV3 channels with higher potency than known TRPV3 activators in Ca²⁺ assays and electrophysiological recordings. TRPV3 activation in the KU-19-19 bladder cancer cells stimulated ATP release, which was abolished by pharmacological TRPV3 blockade, confirming target specificity. Cholesterol supplementation further enhanced TRPV3 activity in KU-19-19 cells, a finding of potential relevance given the known dysregulation of cholesterol metabolism in bladder cancer. These results provide the first evidence of functional TRPV3 expression in bladder cancer cells and suggest that TRPV3 may contribute to Ca²⁺- and cholesterol-dependent signaling pathways. Collectively, these findings support further investigation of TRPV3 as a potential pharmacological target and exploratory biomarker in urothelial carcinoma. SIGNIFICANCE STATEMENT: TRPV3 is an ion channel mainly found in the skin. This study has identified the small molecule AV3-1 as a novel TRPV3 activator. Using AV3-1, this study demonstrates TRPV3 expression in bladder cancer cells. TRPV3 activation in these cells triggers ATP release, a signal potentially promoting cancer progression.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 1","pages":"100096"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introduction of a single carboxylic acid converts the cyclic oligomeric depsipeptide ent-verticilide from a ryanodine receptor 2 (RyR2) inhibitor to RyR2 activator.","authors":"Tri Q Do, Daniel J Blackwell, Abigail N Smith, Madelaine P Thorpe, Robyn T Rebbeck, Derek R Laver, Jeffrey N Johnston, Björn C Knollmann","doi":"10.1016/j.molpha.2025.100086","DOIUrl":"10.1016/j.molpha.2025.100086","url":null,"abstract":"<p><p>Cyclic oligomeric depsipeptides represent a distinct structural class of naturally occurring compounds known for their wide-ranging biological activities. We previously reported that the unnatural form of verticilide (ent-verticilide) inhibits cardiac ryanodine receptor 2 (RyR2) and exhibits antiarrhythmic effects in mice, but its mechanism of action on the RyR2 channel is not known. Here, we collected single-channel recordings in artificial lipid bilayers to elucidate the mechanism of RyR2 modulation by ent-verticilide and its polar side chain analog activert. ent-Verticilide reduced RyR2 activity by increasing the RyR2 mean closed time without changing the RyR2 mean open time, suggesting that ent-verticilide functions as a closed-channel stabilizer. ent-Verticilide exhibited partial inhibition on RyR2 single channels with an IC₅₀ of ∼0.2 μM and a maximal inhibitory efficacy of ∼23%. To explore the effect of a charged residue on ent-verticilide-RyR2 binding, we introduced a terminal carboxylic acid on a single pentyl side chain. The resulting compound lost its inhibitory activity, increased RyR1 and RyR2 single-channel activity, and increased Ca spark frequency. Thus, we named this analog activert (1). Single-channel analysis showed that activert shortened mean closed time without changing mean open time, indicating closed-channel destabilization. Compared with ent-verticilide, activert was ∼100-fold less potent (EC₅₀ ∼ 30 μM) on RyR2 and had low membrane permeability. RyR2 activation was confirmed by [³H]-ryanodine binding and Ca spark assays. Although poor membrane permeability represents an obstacle for therapeutic development, activert serves as a proof-of-concept partial RyR2 activator and a promising scaffold for future structure-activity optimization. SIGNIFICANCE STATEMENT: This study reveals the dual modulatory potential of cyclooligomeric depsipeptides on ryanodine receptor 2, with ent-verticilide acting as a closed-channel stabilizer and its analog, activert, functioning as a closed-channel destabilizer. By leveraging nonnatural enantiomers and rational scaffold modifications, we highlight an underexplored approach to uncover important structure-activity relationships, advancing the development of novel ryanodine receptor 2-targeted therapeutics with potential applications in cardiac arrhythmia management.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 12","pages":"100086"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transient receptor potential vanilloid 3 activation accelerates keratinocyte migration in vitro but not dermal wound healing in vivo.","authors":"Carolin Zosel, Anne-Kathrin Krause, Anne Müglitz, Yan-Qin Zuo, Ute Krügel, Michael Schaefer","doi":"10.1016/j.molpha.2025.100084","DOIUrl":"10.1016/j.molpha.2025.100084","url":null,"abstract":"<p><p>The non-selective Ca²⁺ permeable transient receptor potential vanilloid 3 (TRPV3) ion channel is highly expressed in mouse keratinocytes, where its activation causes an accelerated cell migration and proliferation via an epidermal growth factor receptor-mediated mechanism in vitro. Therefore, TRPV3 has been proposed as a potential target to accelerate dermal wound healing. In this study, we provide an insight into the effects of TRPV3 activation on mouse keratinocytes and skin wound healing in vitro and in vivo using the newly identified activator of TRPV3 1 (AV3-1). To investigate a possible TRPV3-mediated effect on dermal wound closure in vivo, 2 circular wounds were excised on the back of wild-type and TRPV3 knockout mice and topically treated with AV3-1 or the corresponding vehicle. Unexpectedly, the comparison of neither the wound areas nor the histologic parameters yielded a statistically significant difference between wild-type and TRPV3 knockout wounds. Supporting this notion, AV3-1 treatment could not induce any further acceleration of the wound closure compared to vehicle-treated wounds. Therefore, the described TRPV3-mediated acceleration of keratinocyte migration and proliferation in vitro cannot be directly translated into an in vivo context. SIGNIFICANCE STATEMENT: We here show that deficiency of the transient receptor potential vanilloid 3 (TRPV3) channel impairs mouse keratinocyte migration in vitro. In vivo, however, neither TRPV3 deficiency nor TRPV3 activation by the novel activator of TRPV3 activator 1 (AV3-1) had statistically significant effects on healing rates or reepithelialization of skin wounds.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 12","pages":"100084"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive modeling and functional characterization of the ceRNA regulatory network in cisplatin resistance of non-small cell lung cancer.","authors":"Hongyuan Li, Rui Zhang, Wenjun Tao, Yali Cheng, Xianrong Lin, Jun Zhang, Xiangming Cao, Jun Zhou","doi":"10.1016/j.molpha.2025.100087","DOIUrl":"10.1016/j.molpha.2025.100087","url":null,"abstract":"<p><p>Non-small cell lung cancer remains the leading cause of cancer-related mortality worldwide. Cisplatin-based chemotherapy is a primary treatment strategy for non-small cell lung cancer, but acquired drug resistance limits its therapeutic efficacy. Emerging evidence suggests that microRNA-mediated competing endogenous RNA networks play a critical role in regulating anticancer drug resistance. In this study, we initially established a cisplatin sensitivity prediction model that enables the evaluation of cisplatin responsiveness based on patients' transcriptomic profiling. Integrative analysis of cisplatin sensitiveness and the transcriptomic data identified GDF15 and ZDHHC9 as essential drivers of cisplatin resistance. We further constructed the competing endogenous RNA regulatory network centered on these resistance-associated genes. Functional validation determined that hsa-miR-873-5p directly represses GDF15 expression, and its overexpression increased cellular sensitivity to cisplatin, as evidenced by a 35% reduction in half-maximal inhibitory concentration in PC9 cells and a 24% reduction in H226 cells. Our study provides a prediction model for cisplatin responsiveness evaluation and suggests the hsa-miR-873-5p/GDF15 axis as a promising therapeutic target for overcoming cisplatin resistance in non-small cell lung cancer. SIGNIFICANCE STATEMENT: This study develops a predictive model for cisplatin sensitivity in lung cancer and identifies key resistance genes via transcriptomic analysis. The study further reveals the critical hsa-miR-873-5p/GDF15 regulatory axis as a potential biomarker for personalized therapy in patients with non-small cell lung cancer.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 12","pages":"100087"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of constitutive activity of the atypical chemokine receptor 3 by the small-molecule inverse agonist VUF16840.","authors":"Reggie Bosma, Desislava Nesheva, Merel Rijnsburger, Rick Riemens, Justyna M Adamska, Max Meyrath, Simon Mobach, C Maurice Buzink, Suzanne van der Pol, Iwan J P de Esch, Martyna Szpakowska, Maikel Wijtmans, Andy Chevigne, Henry F Vischer, Rob Leurs","doi":"10.1016/j.molpha.2025.100085","DOIUrl":"10.1016/j.molpha.2025.100085","url":null,"abstract":"<p><p>The atypical chemokine receptor 3 (ACKR3) has emerged as a promising drug target for the treatment of cancer, cardiovascular, and autoimmune diseases. In this study, we present the pharmacological characterization of VUF16840, the first small-molecule inverse agonist of ACKR3. VUF16840 effectively displaces CXC chemokine ligand 12 binding to ACKR3 and inhibits chemokine-induced β-arrestin2 recruitment in a concentration-dependent manner. Furthermore, VUF16840 stabilizes the inactive conformation of ACKR3, as demonstrated by its ability to suppress constitutive recruitment of downstream effector proteins. This inverse agonism alters ACKR3 constitutive trafficking, leading to receptor enrichment at the plasma membrane and inhibition of intracellular CXC chemokine ligand 12 uptake. Importantly, VUF16840 exhibits high selectivity for ACKR3 over a broad panel of human chemokine receptors. These findings establish VUF16840 as a potent and selective ACKR3 inverse agonist capable of modulating constitutive and chemokine-induced signaling and internalization events. As such, VUF16840 represents a valuable pharmacological tool for exploring the molecular and translational roles of ACKR3 in both physiologic and pathologic contexts. SIGNIFICANCE STATEMENT: A small molecule inverse agonist of the atypical chemokine receptor 3 (ACKR3), named VUF16840, is characterized in this work. It was shown that VUF16840 was able to inhibit basal as well as ligand-induced ACKR3 activation and, moreover, inhibits the scavenging function of ACKR3.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 12","pages":"100085"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12799421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of hippocampal miR-34c-5p on the age-related discrepancies in susceptibility to traumatic stress in the post-traumatic stress disorder mice model.","authors":"Shuwen Yu, Ting Li, Tingting Li, Bing Gu, Yijing Zhao, Qian Luo, Zhen Wang, Dexiang Liu, Cyrus S H Ho","doi":"10.1016/j.molpha.2025.100090","DOIUrl":"10.1016/j.molpha.2025.100090","url":null,"abstract":"<p><p>Post-traumatic stress disorder is a highly prevalent and debilitating psychiatric condition characterized by symptoms such as depression, anxiety, and persistent fear. Although traumatic stress significantly affects both adolescents and adults, its behavioral and neurobiological impacts may vary substantially across developmental stages. In this study, inescapable foot shock (IFS), a well-established model of traumatic stress that recapitulates aspects of fear memory reactivation, was used to investigate the underlying molecular mechanisms associated with age-dependent responses. Our results demonstrated that adult mice exhibited greater susceptibility to defensive, depressive, and dysphoric behaviors than adolescent mice under identical IFS conditions, as evidenced by adult mice displaying approximately twice the freezing duration compared with adolescents in the conditioned fear test. Concomitant with these behavioral abnormalities, adult mice also showed more pronounced deficits in neuroplasticity and increased neuronal injury relative to their adolescent counterparts. Mechanistically, miR-34c-5p was up-regulated in the hippocampus of adult mice compared with adolescent mice under IFS exposure. Notably, phospholipase C β1, a predicted target of miR-34c-5p and a molecular mediator of neuroplasticity, was markedly upregulated upon miR-34c-5p knockdown, accompanied by activation of the phosphatase and tensin homolog/protein kinase B/cAMP-response element binding protein signaling pathway. Taken together, this study demonstrated that miR-34c-5p might serve as a risk susceptibility factor accompanied by age alterations in the traumatic stress mice model. By modulating the phospholipase C β1/phosphatase and tensin homolog/protein kinase B/cAMP-response element binding protein signaling cascade, miR-34c-5p contributes to the observed age-related differences in affective disorders after IFS exposure. Hence, miR-34c-5p may act as a potential therapeutic target for mitigating post-traumatic stress disorder susceptibility across different developmental stages. SIGNIFICANCE STATEMENT: This study provides evidence that age-related vulnerability discrepancies were markedly presented in mice under inescapable foot shock exposure. MiR-34c-5p might serve as a susceptibility factor with age alterations in traumatic stress mice models. These findings reveal mechanisms by which miR-34c-5p/phospholipase C β1 axis may regulate age-dependent susceptibility differences in mice exposed to inescapable foot shock.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 12","pages":"100090"},"PeriodicalIF":3.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145864096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}