Molecular Pharmacology最新文献

{"title":"Commentary on the fourth Transatlantic G Protein-Coupled Receptor Symposium for early-career investigators.","authors":"Judith Alenfelder, Ian B Chronis, Katarina Nemec, Aida Shahraki","doi":"10.1016/j.molpha.2025.100052","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100052","url":null,"abstract":"<p><p>The fourth Transatlantic Early-Career Investigator GPCR Symposium-held on September 5-6, 2024-was a virtual conference intended to provide an accessible, low-cost opportunity for early-stage researchers in the field of G protein-coupled receptor biology to share their work and engage with colleagues. This commentary discusses the symposium's structure and successes, as well as suggesting areas of improvement for future iterations. SIGNIFICANCE STATEMENT: The fourth Transatlantic Early-Career Investigator GPCR Symposium provided an accessible platform for early-career investigators to present their research and engage with peers and senior scientists. By leveraging a virtual format, the symposium addressed the financial and logistical barriers of traditional conferences, fostering scientific discourse and future collaboration. The event's structure facilitated networking opportunities and highlighted the importance of integrating diverse technologies in GPCR research. This symposium's success underscores the need for continued innovation in creating inclusive and impactful scientific forums.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100052"},"PeriodicalIF":3.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528838","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":"An overview of autophagy inhibition as a potential clinical strategy in cancer therapy.","authors":"Ahmed M Elshazly, Nayyerehalsadat Hosseini, Aya A Elzahed, David A Gewirtz","doi":"10.1016/j.molpha.2025.100056","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100056","url":null,"abstract":"<p><p>Autophagy is a cellular process responsible for the recycling of misfolded proteins and damaged organelles, contributing to cellular homeostasis and energy production. Tumor cells often exploit this mechanism, particularly through the form of autophagy that is cytoprotective, to survive endogenous and exogenous stress and resist chemotherapeutic agents as well as radiation therapy. Although several autophagy inhibitors have been developed to block the protective form of autophagy, their clinical application is often limited due to a lack of selectivity and significant side effects. In addition to the cytoprotective form, cytotoxic, cytostatic, and nonprotective functions of autophagy have been identified. In this review, we summarize a series of publications, largely from our own laboratory, exploring how various antineoplastic agents trigger different forms of autophagy and assess whether autophagy inhibition or modulation could serve as an effective adjuvant approach to enhance therapeutic responses. Furthermore, we discuss recent advancements in the autophagy field and the potential for improving cancer therapeutic strategies. SIGNIFICANCE STATEMENT: This work provides an overview of our previous work investigating the different forms of autophagy induced by various antineoplastic modalities across different tumor models. The purpose of this effort is to draw tentative conclusions regarding the potential of targeting autophagy as a strategy to enhance the efficacy of these therapeutic agents. Additionally, we offer insights into recent advances in the autophagy field.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 8","pages":"100056"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668016","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":"Investigation of the binding mode of clobenprobit at CXCR4 and development of novel anti-inflammatory compounds with enhanced activity and minimal antagonist effects.","authors":"Birgit Caspar, Nassima Bekaddour, Séverine Grinberg, Dominique Cathelin, Ivana Stoilova, Stephane Giorgiutti, Vincent Gies, Anne-Sophie Korganow, Nicolas Pietrancosta, Didier Roche, Vincent Rodeschini, Jean-Philippe Herbeuval","doi":"10.1016/j.molpha.2025.100055","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100055","url":null,"abstract":"<p><p>IT1t and clobenprobit (CB) have been shown to act as anti-inflammatory compounds in dependence of the chemokine receptor C-X-C receptor type 4 (CXCR4) in model systems. Here, the direct interaction between CB and CXCR4 is demonstrated via in silico modeling and bioluminescence resonance energy transfer binding assays at wild-type and mutant versions of CXCR4. The binding site is compared with those of IT1t and AMD3100, two well known CXCR4 ligands. In contrast to AMD3100, IT1t also displays an anti-inflammatory signaling effect. Ligands observed to have this anti-inflammatory effect seem to bind into the minor pocket of CXCR4 impacting the binding of the endogenous ligand CXCL12 only at high concentrations. Based on this observation further compounds thought to bind the minor pocket of CXCR4 were designed and screened for their anti-inflammatory potency. The best of these compounds, NP1411, was tested in its ability to inhibit CXCL12 mediated G protein activation as well as CXCL12 and CB binding. SIGNIFICANCE STATEMENT: This study presents a comprehensive investigation into the binding site of anti-inflammatory compounds at the C-X-C receptor type 4 receptor using in silico and in vitro ligand binding approaches. This opens the opportunity for the development of further therapeutic agents with higher potency and/or efficacy as presented in an initial test at the end of the publication.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 8","pages":"100055"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663968","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":"Chemokine receptors - Exemplifying functional divergence in G protein-coupled receptors.","authors":"Omolade Otun, Sébastien Granier, Thierry Durroux, Cherine Bechara","doi":"10.1016/j.molpha.2025.100053","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100053","url":null,"abstract":"<p><p>G protein-coupled receptors are known for their ability to generate a wide range of functional responses through interaction with various intracellular partners. This versatility is particularly evident within the chemokine receptor family, where conventional receptors signal primarily through classic G protein-coupled pathways while atypical chemokine receptors appear not to possess such ability but instead couple to alternative intracellular partners such as β-arrestins. Functional diversity in signaling presents unique opportunities for drug development, allowing different pathways to be selectively targeted to meet specific therapeutic needs. This minireview explores the mechanisms by which G protein-coupled receptor signaling, particularly within the chemokine receptor family, can be diversified at the modulatory, transmembrane, and intracellular levels. SIGNIFICANCE STATEMENT: This minireview explores how signaling in the chemokine receptor family diversifies at the ligand, transmembrane, and intracellular levels. This functional diversity presents unique opportunities for drug development by selectively targeting distinct pathways.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100053"},"PeriodicalIF":3.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619044","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":"Corrigendum to \"Functional Interaction between Transient Receptor Potential V4 Channel and Neuronal Calcium Sensor 1 and the Effects of Paclitaxel\".","authors":"","doi":"10.1016/j.molpha.2025.100051","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100051","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 7","pages":"100051"},"PeriodicalIF":3.2,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275348","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":"Extracellular ATP increases agonist potency and reduces latency at class B G protein-coupled receptors.","authors":"Shuying Zhu, Alice Yuan, Tristan Duffy, Brandon H Kim, Takeaki Ozawa, S Jeffrey Dixon, Peter Chidiac","doi":"10.1016/j.molpha.2025.100040","DOIUrl":"10.1016/j.molpha.2025.100040","url":null,"abstract":"<p><p>Class B G protein-coupled receptors (GPCRs) are peptide hormone receptors, many of which, such as parathyroid hormone receptor 1, calcitonin receptor (CTR), and corticotropin-releasing factor receptor (CRF1R), are established or emerging therapeutic targets. Previously, we showed that extracellular ATP and related molecules act as positive modulators of parathyroid hormone receptor 1 signaling through an undefined mechanism. Here, we investigated whether ATP enhances signaling by other members of the class B family of GPCRs. Cyclic AMP (cAMP) accumulation was monitored in cells expressing a bioluminescent sensor. Extracellular ATP, which did not induce cAMP accumulation on its own, potentiated agonist-induced cAMP accumulation mediated by CTR, CRF1R, calcitonin receptor-like receptor, pituitary adenylyl cyclase-activating polypeptide receptor 1, and vasoactive intestinal peptide receptors 1 and 2. ATP induced a comparable effect on agonist-stimulated recruitment of β-arrestin to pituitary adenylyl cyclase-activating polypeptide receptor 1. Depending on the receptor and agonist, ATP increased agonist potency by up to 50-fold. The enhancing effect of ATP was mimicked by cytidine 5'-monophosphate, ruling out involvement of purinergic receptors, ATPase activity, or ectokinase activity. For certain receptors (CTR, calcitonin receptor-like receptor + receptor activity-modifying protein 1, and CRF1R), there were temporal lags of up to 30 minutes following agonist application before maximal rates of cAMP accumulation were reached. Lag duration decreased with increasing agonist concentration, suggesting an inverse relationship with receptor occupancy. ATP virtually abolished this temporal lag, even at relatively low agonist concentrations. Thus, ATP both increases the potency of orthosteric agonists at class B GPCRs and reduces latency for adenylyl cyclase activation. SIGNIFICANCE STATEMENT: In addition to acting as a positive modulator of PTH1R signaling, extracellular ATP increases the potency of orthosteric agonists at other class B GPCRs and reduces the latency for adenylyl cyclase activation. Further insight into the precise mechanism of ATP-mediated potentiation of class B GPCR signaling may identify new targets for the development of therapeutic agents aimed at the treatment of endocrine disorders.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100040"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086382","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":"Bryostatins 1 and 3 inhibit TRPM8 and modify TRPM8- and TRPV1-mediated lung epithelial cell responses to a proinflammatory stimulus via protein kinase C.","authors":"Lili Sun, John G Lamb, Changshan Niu, Samantha N Serna, Erin Gail Romero, Cassandra E Deering-Rice, Eric W Schmidt, Martin Golkowski, Christopher A Reilly","doi":"10.1016/j.molpha.2025.100042","DOIUrl":"10.1016/j.molpha.2025.100042","url":null,"abstract":"<p><p>Bryostatin 1 is a protein kinase C (PKC α, β, δ) activator with anti-inflammatory effects. We hypothesized that bryostatins 1 and 3 could modulate transient receptor potential (TRP) channels via PKC and alter TRP-mediated proinflammatory signaling in lung epithelial cells challenged with a proinflammatory stimulus, coal fly ash (CFA). Bryostatins 1 and 3 inhibited icilin-induced calcium flux in HEK-293 cells overexpressing full-length human transient receptor potential melastatin-8 (TRPM8) but did not inhibit activation by menthol or the activities of human transient receptor potential ankyrin 1, transient receptor potential vanilloid 1 (TRPV1), TRPV3, or TRPV4; mouse and rat TRPM8 were less sensitive to inhibition. TRPM8 inhibition was transient (<24 hours), PKC-dependent, and involved differential phosphorylation of amino acids T17, S27, S850, and S1040. CFA particles stimulate interleukin-8 (IL8) and C-X-C motif chemokine ligand 1 (CXCL1) expression by human bronchial epithelial cells via activation of truncated TRPM8 (TRPM8-Δ801) and TRPV1. However, bryostatins 1 and 3 altered IL8 and CXCL1 mRNA expression with and without CFA treatment. At 4 hours, the bryostatins also suppressed TRPM8 mRNA and induced TRPV1 mRNA, which reversed at 24 hours. These effects were reversed by pharmacological inhibition of PKC isoforms (α, ζ, ε, or η) but not δ, implying a network comprised of presumably PKCα, TRPM8-Δ801, and TRPV1 that regulates IL8 and CXCL1 expression by airway epithelial cells. Finally, an unexpected interaction between TRPV1 and TRPM8, but not TRPM8-Δ801, was also identified. Specifically, the coexpression of TRPM8 and TRPV1 reduced TRPM8 expression and activity, which was reversed by TRPV1 inhibition, revealing novel mechanisms by which bryostatins and PKC affect TRP channel signaling in lung epithelial and potentially other cell types. SIGNIFICANCE STATEMENT: Bryostatins 1 and 3 selectively and transiently inhibit human TRPM8 activity via protein kinase C-dependent phosphorylation and temporally modify the expression and induction of interleukin-8 and C-X-C motif chemokine ligand 1 in lung epithelial cells by regulating TRPV1 and TRPM8 expression. This regulatory nexus may have therapeutic potential for treating airway inflammation.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100042"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086394","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":"Research approaches for exploring the hidden conversations of G protein-coupled receptor transactivation.","authors":"Janbolat Ashim, Min Jae Seo, Sangho Ji, Joongyu Heo, Wookyung Yu","doi":"10.1016/j.molpha.2025.100043","DOIUrl":"10.1016/j.molpha.2025.100043","url":null,"abstract":"<p><p>G protein-coupled receptor (GPCR) signaling is a crucial physiological mechanism that encompasses a wide range of signaling phenomena. Although traditional GPCR signaling involves G protein or arrestin-related activation, other modes such as biphasic activation, dimer or oligomeric activation, and transactivation have also been observed. Herein, we focus on the increasingly recognized process of GPCR-transactivation. Transactivation refers to the ability of GPCRs to activate other receptor types, especially receptor tyrosine kinases, without engaging their own specific ligands. This cross-talk between GPCRs and other receptors facilitates the integration of multiple signaling pathways, thereby regulating diverse cellular responses, which underscores its physiological significance. In this review, we provide a comprehensive overview of the role of GPCR-transactivation in physiology. We also discuss the growing interest in this field and examine the various tools available for studying transactivation. Additionally, we highlight recent advancements in emerging tools and their application to GPCR-transactivation research. Finally, we propose future research directions and consider the potential impact of new technologies in this rapidly evolving field. SIGNIFICANCE STATEMENT: G protein-coupled receptor transactivation plays a key role in integrating multiple signaling pathways by activating other proteins, like receptor tyrosine kinases, without binding their specific ligands. Here, we focus on the significance of transactivation and the various approaches used to study this phenomenon.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100043"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191973","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":"Special section: William A. Catterall Memorial Issue - Mechanisms of Electrical Excitability.","authors":"Lori L Isom","doi":"10.1016/j.molpha.2025.100044","DOIUrl":"10.1016/j.molpha.2025.100044","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100044"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094171","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":"Fat traffic control: S-acylation in axonal transport.","authors":"Amelia H Doerksen, Nisandi N Herath, Shaun S Sanders","doi":"10.1016/j.molpha.2025.100039","DOIUrl":"10.1016/j.molpha.2025.100039","url":null,"abstract":"<p><p>Neuronal axons serve as a conduit for the coordinated transport of essential molecular cargo between structurally and functionally distinct subcellular compartments via axonal molecular machinery. Long-distance, efficient axonal transport of membrane-bound organelles enables signal transduction and neuronal homeostasis. Efficient axonal transport is conducted by dynein and kinesin ATPase motors that use a local ATP supply from metabolic enzymes tethered to transport vesicles. Molecular motor adaptor proteins promote the processive motility and cargo selectivity of fast axonal transport. Axonal transport impairments are directly causative or associated with many neurodegenerative diseases and neuropathologies. Cargo specificity, cargo-adaptor proteins, and posttranslational modifications of cargo, adaptor proteins, microtubules, or the motor protein subunits all contribute to the precise regulation of vesicular transit. One posttranslational lipid modification that is particularly important in neurons in regulating protein trafficking, protein-protein interactions, and protein association with lipid membranes is S-acylation. Interestingly, many fast axonal transport cargos, cytoskeletal-associated proteins, motor protein subunits, and adaptors are S-acylated to modulate axonal transport. Here, we review the established regulatory role of S-acylation in fast axonal transport and provide evidence for a broader role of S-acylation in regulating the motor-cargo complex machinery, adaptor proteins, and metabolic enzymes from low-throughput studies and S-acyl-proteomic data sets. We propose that S-acylation regulates fast axonal transport and vesicular motility through localization of the proteins required for the motile cargo-complex machinery and relate how perturbed S-acylation contributes to transport impairments in neurological disorders. SIGNIFICANCE STATEMENT: This review investigates the regulatory role of S-acylation in fast axonal transport and its connection to neurological diseases, with a focus on the emerging connections between S-acylation and the molecular motors, adaptor proteins, and metabolic enzymes that make up the trafficking machinery.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100039"},"PeriodicalIF":3.2,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010183","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}