Molecular Pharmacology最新文献

{"title":"Corrigendum to \"The Natural Compound Withaferin A Covalently Binds to Cys239 of β-Tubulin to Promote Tubulin Degradation\".","authors":"","doi":"10.1016/j.molpha.2025.100045","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100045","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100045"},"PeriodicalIF":3.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079133","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":"https://doi.org/10.1016/j.molpha.2025.100044","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100044"},"PeriodicalIF":3.2,"publicationDate":"2025-05-06","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":"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":"https://doi.org/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":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoprenaline shows unique kinase dependencies in stimulating β₁AR-β-arrestin2 interaction compared to endogenous catecholamines.","authors":"Edda S F Matthees, Luca E Kletzin, Arnelle Löbbert, Jana S Hoffmann, Carolin Große, Alvar D Gossert, Carsten Hoffmann","doi":"10.1016/j.molpha.2025.100041","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100041","url":null,"abstract":"<p><p>The β1-adrenergic receptor (β₁AR) is an essential G protein-coupled receptor in the heart. Its dysregulation represents a hallmark of cardiac diseases. Studies have identified a unique mode of β-arrestin interaction, where β₁AR briefly engages with β-arrestins before catalytically accumulating them at the plasma membrane (PM) independently of the receptor. Although receptor phosphorylation crucially impacts β-arrestins, the contributions of specific kinases vital in β₁AR regulation remain unclear. Here, we employed G protein-coupled receptor kinase (GRK) GRK2/3/5/6 knockout cells and the protein kinase A inhibitor H89 in bioluminescence resonance energy transfer-based assays to systematically assess GRKs and protein kinase A in direct β-arrestin2 recruitment to β₁AR and β-arrestin2 translocation to the PM. Furthermore, we compared the effects of the synthetic agonist isoprenaline with the endogenous catecholamines: epinephrine and norepinephrine. We observed pronounced differences in their kinase dependencies to mediate β-arrestin2 translocation to the PM. Upon isoprenaline stimulation, GRKs strongly influenced β-arrestin2 translocation to the PM but had no effect on direct β-arrestin2 recruitment to β₁AR. Additionally, in a GRK2-specific context, protein kinase A inhibition primarily reduced the efficacy of isoprenaline for β-arrestin2 translocation, whereas for GRK5, it decreased potency. Strikingly, these kinase-dependent effects were absent for epinephrine and norepinephrine, suggesting distinct underlying molecular mechanisms for β-arrestin2 accumulation at the PM. This observation could be explained by agonist-specific differences in receptor conformational rearrangements, as suggested by distinct changes in the NMR spectra of β₁AR. Our findings highlight that synthetic and endogenous ligands induce distinct molecular mechanisms in β₁AR regulation, emphasizing the need to consider these differences when translating molecular insights into physiological contexts. SIGNIFICANCE STATEMENT: Our findings reveal mechanistic differences in β1-adrenergic receptor-mediated catalytic activation of β-arrestin2 by synthetic and endogenous agonists, driven by distinct G protein-coupled receptor kinases and protein kinase A dependencies. Although β-arrestin2 translocation to the PM occurred to similar extents with isoprenaline, epinephrine, and norepinephrine, kinase involvement was crucial only upon Iso stimulation of β1-adrenergic receptor. By elucidating these ligand-specific pathways, this study advances our understanding of β1-adrenergic receptor signaling and regulation while additionally highlighting the importance of considering these differences when translating molecular insights into pathophysiological contexts.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 6","pages":"100041"},"PeriodicalIF":3.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144028297","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":"https://doi.org/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":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2- Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling\".","authors":"","doi":"10.1016/j.molpha.2025.100038","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100038","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100038"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143971671","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 \"Novel Thiosemicarbazones Inhibit Lysine-Rich Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) Coisolated (LYRIC) and the LYRIC-Induced Epithelial- Mesenchymal Transition via Upregulation of N-Myc Downstream-Regulated Gene 1 (NDRG1)\".","authors":"","doi":"10.1016/j.molpha.2025.100037","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100037","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100037"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013405","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 \"Targeting the Metastasis Suppressor, NDRG1, Using Novel Iron Chelators: Regulation of Stress Fiber-Mediated Tumor Cell Migration via Modulation of the ROCK1/pMLC2 Signaling Pathway\".","authors":"","doi":"10.1016/j.molpha.2025.100036","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100036","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100036"},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031891","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":"Non-nutritive sweeteners in food-drug interactions: An overview of current evidence.","authors":"Laura Danner, Kale Kroenke, Stephanie Olivier-Van Stichelen","doi":"10.1016/j.molpha.2025.100035","DOIUrl":"https://doi.org/10.1016/j.molpha.2025.100035","url":null,"abstract":"<p><p>Food-drug interactions occur when the presence of foods interferes with the absorption, distribution, metabolism, or excretion of pharmaceuticals. Specific compounds within foods, like certain phytochemicals from grapefruit, have been known to precipitate food-drug interactions for decades, leading to guidance from physicians and pharmacists about patients' dietary restrictions while taking certain drugs. Although approved by the Food and Drug Administration, high-intensity non-nutritive sweeteners (NNS) share qualities with drugs that suggest the potential for similar interactions. In this minireview, we have reviewed 5 of the most popular NNS, including saccharin, aspartame, acesulfame potassium, sucralose, and stevia, and detail their drug-like qualities, regulatory status, pharmacokinetics, and primary research articles containing evidence of NNS interacting with drug absorption, distribution, metabolism, and excretion. Although studies varied widely in concentration ranges for NNS, model systems, and methods, all NNS included in this review were found to have known interactions with mediators of absorption, distribution, metabolism, and excretion from studies conducted after their Food and Drug Administration approval or generally recognized as safe designation. We have highlighted essential gaps in the literature and recommend the scientific community actively research NNS as food additives that may interact with drugs. SIGNIFICANCE STATEMENT: Food-drug interactions are a growing concern in Western societies where polypharmacy and ultraprocessed foods and beverages are increasingly common. High-intensity non-nutritive sweeteners bear structural similarities to pharmaceuticals, and evidence suggests they interact with mediators of drug pharmacokinetics. This minireview highlights the interactions uncovered thus far and serves as a call to action for the scientific community to establish rigorous, consistent testing that will enable updated safety guidelines for consumers.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"107 5","pages":"100035"},"PeriodicalIF":3.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972015","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}