Molecular Pharmacology最新文献

{"title":"The molecular geography of cell signaling diseases.","authors":"John D Scott, Carmen W Dessauer","doi":"10.1016/j.molpha.2026.100151","DOIUrl":"10.1016/j.molpha.2026.100151","url":null,"abstract":"<p><p>Precision pharmacology has emerged from advances in cell biology, microscopy, and signal transduction, revealing that intracellular communication is highly organized within spatially restricted compartments. Hence, therapeutic approaches that manage disease-associated signaling steps within defined subcellular microdomains are attractive precision pharmacology targets. A-kinase anchoring proteins coordinate this remarkable level of spatial organization by clustering protein kinase A with phosphatases and cAMP effector proteins. These signaling islands direct second messenger responses toward selected substrates while restricting inappropriate crosstalk. Perturbation of A-kinase anchoring protein-directed signaling contributes to cardiovascular disease, endocrine dysfunction, cancer progression, chronic pain, and neurodegeneration. Agents that selectively modulate or dismantle pathological signaling complexes may offer a less invasive means to therapeutically exploit the molecular geography of diseased cells, particularly if used in combination with molecular glues, chimera-targeted protein degradation targeted protein degradation, and selective kinase inhibitors. This article is a foreword for a series of 4 minireviews commissioned by the journal from speakers at the 2025 ASPET Axelrod Symposium on spatial cAMP signaling. These contributions examine how pathological perturbations in A-kinase anchoring protein-mediated signaling networks contribute to a diverse spectrum of disease processes, including maladaptive cardiac remodeling, endocrine hyperfunction, nociceptor sensitization, and synaptic failure in AD. SIGNIFICANCE STATEMENT: Intracellular signaling is a fundamental process that governs cellular physiology and disease pathogenesis. This miniseries highlights how A-kinase anchoring proteins assemble signaling nanodomains to locally control second messenger-responsive enzymes in the cardiovascular, endocrine, and nervous systems. A-kinase anchoring protein macromolecular assemblies are emerging venues for precision pharmacology.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100151"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148970271","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 integrated structural and functional profiling approach uncovers the mechanisms of pregnane X receptor binding and activation by pharmaceutical and environmental compounds.","authors":"Quentin Derosa, Coralie Carivenc, Savannah Sirounian, Marina Grimaldi, Abdelhay Boulahtouf, Vanessa Delfosse, Patrick Balaguer, William Bourguet","doi":"10.1016/j.molpha.2026.100140","DOIUrl":"10.1016/j.molpha.2026.100140","url":null,"abstract":"<p><p>The pregnane X receptor (PXR) is a key chemosensory protein that helps the organism adapt to its chemical environment. Indeed, humans are continuously exposed to a wide range of external chemicals, known as xenobiotics, which include environmental pollutants, food components, cosmetics, and pharmaceuticals. PXR has the unique property to sense a large variety of xenobiotics and regulate the expression of detoxifying enzymes and transporters, facilitating the clearance of these chemicals. However, prolonged activation of this pathway can lead to negative effects, such as drug-drug interactions, chemoresistance, endocrine disruption, a heightened risk of metabolic diseases, or enhanced cell growth and tumor aggressiveness. Understanding how PXR interacts with xenobiotics is crucial for predicting, assessing, and preventing the potential impacts of these chemicals on human health. Here, we present the structural and functional analysis of the interaction of PXR with 2 approved drugs (nimodipine and liranaftate), a natural flavor commonly used in cosmetics and the food industry (sclareol), and an environmentally relevant halogenated derivative of the emblematic endocrine disruptor bisphenol A (2,2'-dichlorobisphenol A). Cell-based assays show that these 4 compounds display different PXR binding potencies, stimulate the expression of key target genes related to drug metabolism and cell proliferation, and promote colon cancer cell proliferation to varying degrees. Crystallographic analysis reveals their distinct mechanisms of binding to PXR. The integrated functional and structural characterization pipeline we have established yields critical insights for both environmental risk assessment and the rational development of industrial and pharmaceutical compounds with minimal harmful PXR activity. SIGNIFICANCE STATEMENT: The pregnane X receptor is an off-target of many pharmaceuticals and industrial chemicals whose activation is associated with clinically relevant drug-drug interactions. This study describes a pipeline for the identification and characterization of pregnane X receptor ligands, designed to support environmental risk assessment and the informed design of safer substitutes.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100140"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549882","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":"Roles of the phosphorylation sites of distinct α_1A-adrenergic receptor domains.","authors":"Rocío Alcántara-Hernández, David A Hernández-Espinosa, Gabriela García-Merino, J Adolfo García-Sáinz","doi":"10.1016/j.molpha.2026.100143","DOIUrl":"10.1016/j.molpha.2026.100143","url":null,"abstract":"<p><p>Phosphorylation participates in the signaling, localization, and trafficking of G protein-coupled receptors. In this study, the amino acids known to be phosphorylated in α_1A-adrenergic receptors were substituted with nonphosphorylatable residues in intracellular loop 3 (IL3) mutant, the carboxyl terminus (CTerm) mutant, and both structural regions (IL3-CTerm mutant). Their functions were compared with those of the wild-type (WT) receptor. Agonist- and protein kinase C-induced receptor phosphorylation was markedly decreased in the IL3-CTerm mutant, confirming the major roles of both domains in this process. Surprisingly, the substitutions did not affect the agonist-induced increase in intracellular calcium. Similarly, neither the WT nor the mutant receptors were desensitized by protein kinase C activation; however, agonist stimulation markedly desensitized the receptors, and this effect was diminished in the IL3 mutant, suggesting a role for this domain in this process. Extracellular signal-regulated kinase 1/2 phosphorylation was strong but transient in cells expressing the WT receptor, strong and sustained in those expressing the CTerm mutant, and markedly reduced in those expressing the IL3 and IL3-CTerm mutants. These findings suggest that IL3 phosphorylation sites modulate extracellular signal-regulated kinase activity. A weak and slow agonist-induced receptor-β-arrestin interaction was detected in cells expressing the WT receptor but was barely detectable in any of the mutants. Consistent with these findings, agonist- and phorbol ester-induced receptor internalization was observed in cells expressing the WT receptor but was markedly decreased in cells expressing the distinct mutants. SIGNIFICANCE STATEMENT: Phosphorylation sites in both intracellular loop 3 (IL3) and carboxyl terminus domains affect receptor function in distinct but complementary ways. The IL3 mutant showed decreased agonist-induced desensitization of the calcium response and agonist-activated extracellular signal-regulated kinase phosphorylation. α_1A-Adrenergic receptor internalization and interaction with β-arrestin were decreased in all mutants containing phosphorylation site substitutions. Phosphorylation sites in the IL3 and carboxyl terminus domains appear to be functionally relevant for this receptor. The approach employed could be used to expand knowledge on other G protein-coupled receptors.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100143"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850923","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":"A-kinase anchoring protein complexes and cAMP signaling within the dorsal root ganglia in chronic pain.","authors":"Anibal Garza-Carbajal, Carmen W Dessauer","doi":"10.1016/j.molpha.2026.100148","DOIUrl":"10.1016/j.molpha.2026.100148","url":null,"abstract":"<p><p>cAMP signaling is a central regulator of dorsal root ganglion neuron excitability, with spatial and functional specificity conferred by A-kinase anchoring proteins (AKAPs). Here, we examine how cAMP signaling and AKAP-associated signalosomes control nociceptor sensitization and contribute to persistent pain states. We emphasize differential roles of adenylyl cyclase isoforms in dorsal root ganglion neurons and their regulation within AKAP79/150 complexes that coordinate protein kinases, ion channels, and phosphatases to modulate excitability and synaptic plasticity. In pathological conditions such as spinal cord injury, these networks promote sustained hyperexcitability and diminished opioid potency. In particular, AKAP79/150-associated L-type voltage-gated calcium channels are central to circuits involving local calcium influx, extracellular signal-regulated kinase activation, and cAMP signaling that reduce sensitivity to inhibitory Gαi and thus opioids in pathological pain states. These insights identify AKAP-centered signaling hubs as critical integrators of nociceptor function and mechanistically link altered cAMP compartmentation to reduced analgesic efficacy. Targeting these complexes, including modulation of calcium channel activity, represents a promising strategy to restore opioid sensitivity and improve treatment of chronic pain. SIGNIFICANCE STATEMENT: Chronic neuropathic pain remains difficult to treat and is often refractory to standard therapies. This review highlights a critical need to define the molecular mechanisms that sustain nociceptor hyperexcitability. A-kinase anchoring protein-organized signaling complexes in sensory ganglia spatially coordinate adenylyl cyclase, calcium channels, and downstream effectors to drive persistent excitability and reduced opioid sensitivity. Thus, these signalosomes represent promising targets for more effective pain therapeutics.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100148"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850948","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":"Anchored kinase and phosphatase signaling networks in amyloid β-induced synaptic dysfunction.","authors":"Laura Koek, Ha-Neul Jo, Matthew J Kennedy, Mark L Dell'Acqua","doi":"10.1016/j.molpha.2026.100141","DOIUrl":"10.1016/j.molpha.2026.100141","url":null,"abstract":"<p><p>Impaired excitatory synaptic function and synapse loss are early hallmarks of Alzheimer's disease (AD). There is strong biochemical, genetic, physiological, and anatomical evidence that the accumulation of soluble amyloid beta (Aβ) oligomers in the brain leads to AD-related synapse dysfunction and cognitive impairment. Long-term potentiation (LTP), a key form of synaptic plasticity for learning and memory, is disrupted in several mouse models harboring familial early-onset AD-linked mutations that lead to Aβ accumulation, and even acute applications of Aβ oligomers block LTP within minutes and promote synapse loss within days. How does Aβ cause such profound synaptic dysfunction? It is increasingly appreciated that Aβ hijacks normal synaptic signaling pathways involved in plasticity, biasing them toward long-term depression (LTD) and eventual synapse elimination. LTP and LTD in the hippocampus are ultimately driven by insertion and removal of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from synapses, respectively, in response to Ca²⁺ signals generated by N-methyl-d-aspartate-type glutamate receptors or L-type voltage-gated Ca²⁺ channels. Central to the signaling pathways regulating AMPAR trafficking during LTP and LTD is a postsynaptic Ser/Thr kinase/phosphatase signaling network that is coordinated by the scaffold protein A-kinase anchoring protein (AKAP) 79/150 (human79/rodent150; AKAP5/Akap5 gene). This AKAP-organized signalosome includes N-methyl-d-aspartate-type glutamate receptors, AMPARs, L-type voltage-gated Ca²⁺ channels, G-protein-coupled receptors, adenylyl cyclase, the cyclic adenosine mono-phosphate (cAMP)-dependent protein kinase, and the Ca²⁺-calmodulin-dependent protein phosphatase 2B/calcineurin. This minireview will highlight recent findings that Gαs-coupled β₂-adrenergic and Gαq-coupled group 1 metabotropic glutamate (mGlu1/5) receptors signal through AKAP79/150-anchored cAMP-dependent protein kinase and protein phosphatase 2B/calcineurin to mediate multiple aspects of Aβ synaptotoxicity. SIGNIFICANCE STATEMENT: Recent studies reveal that amyloid beta engages A-kinase anchoring protein-scaffolded G-protein-coupled receptor signaling pathways to disrupt synaptic plasticity and promote synapse loss. These pathways contain several potential therapeutic targets involved in both local cAMP-dependent protein kinase and calcineurin/protein phosphatase 2B (CaN) signaling that regulates L-type voltage-gated calcium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and N-methyl-d-aspartate receptors to impair synaptic plasticity as well as distal CaN signaling to the nucleus that regulates gene expression to drive synapse loss.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100141"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549814","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":"Panoramic characterization of proposed ligands for GPR3: oleoylethanolamide as a pharmacological chaperone.","authors":"Ian T Pyne, Alex J Roy, Sophia Boraschi, Sanjit S Hajgude, Randy A Hall","doi":"10.1016/j.molpha.2026.100146","DOIUrl":"10.1016/j.molpha.2026.100146","url":null,"abstract":"<p><p>G protein-coupled receptor 3 (GPR3) is a constitutively active G protein-coupled receptor known to regulate β-amyloid deposition in the brain and metabolism in brown adipose tissue. Although multiple compounds have been proposed to activate GPR3 signaling, it is still considered an orphan receptor. Recently, structural evidence revealed a hydrophobic tunnel in GPR3, suggesting that a lipid may be an endogenous agonist for GPR3. We sought to characterize the reported agonists for GPR3 to determine which might be authentic agonists and found that only the synthetic ligand, diphenyleneiodonium chloride, and the endogenous lipids, oleoylethanolamide (OEA) and oleamide, stimulated cAMP generation in a GPR3-dependent manner. Although treatment of cells with diphenyleneiodonium chloride stimulated rapid cAMP generation, we observed gradual increases in GPR3 activation over multiple hours after OEA treatment. Additionally, we found that chronic stimulation with OEA caused an increase in GPR3 cell surface expression. Coupled with the slow activation kinetics of OEA-stimulated GPR3 signaling, these findings suggest that OEA does not behave strictly as a classical agonist for GPR3. Indeed, we found that the OEA-mediated increase in GPR3 on the cell surface can be blocked by inhibiting receptor forward trafficking through the endoplasmic reticulum and Golgi, which positions OEA as a pharmacological chaperone that increases GPR3 signaling by promoting receptor trafficking to the cell surface. These findings suggest a novel mechanism for the regulation of the constitutively active receptor GPR3, whereby the amount of receptor at the plasma membrane, and therefore, the receptor's signaling activity, can be regulated by lipid binding in the endoplasmic reticulum/Golgi. SIGNIFICANCE STATEMENT: This study proposes a novel mechanism for the regulation of the activity of the G protein-coupled receptor, G protein-coupled receptor 3. This study found that the endogenous lipid oleoylethanolamide functions as a pharmacological chaperone by promoting the accumulation of G protein-coupled receptor 3 at the plasma membrane through increased forward trafficking, thereby inducing increased receptor signaling activity.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 8","pages":"100146"},"PeriodicalIF":3.0,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148865695","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":"Regulation of organic anion transporting polypeptide 1B1 transport function by lysine deacetylase 6.","authors":"Vikram Aditya, Vishakha Tambe, Pascaline Niyonshuti, Ruhul Kayesh, Erik J Soderblom, Xiaohong Mary Zhang, Chao Xu, Wei Yue","doi":"10.1016/j.molpha.2026.100132","DOIUrl":"10.1016/j.molpha.2026.100132","url":null,"abstract":"<p><p>Hepatic transport protein organic anion transporting polypeptide 1B1 (OATP1B1) is a key determinant of drug-drug interactions. We reported OATP1B1 lysine acetylation recently, however, the lysine deacetylase (KDAC), also known as histone deacetylase (HDAC), involved in its deacetylation remains uninvestigated. This study determined the role of KDAC6/HDAC6, a major cytosolic KDAC, on OATP1B1 acetylation and transport function. Loss-of-function of KDAC6 by CRISPR/Cas9-mediated knockout in HEK293T cells or by treatment with the selective KDAC6 inhibitor tubacin (TBC) (5 μM, 24 hours) in transporter-expressing HEK293 cells markedly reduces OATP1B1-mediated transport of [³H]estradiol-17-ß-D-glucuronide to 0.62 ± 0.095- and 0.28 ± 0.007-fold of control, respectively. TBC treatment did not affect OATP1B1 mRNA, protein levels and colocalization with plasma membrane marker Na/K-ATPase, suggesting a regulation at a post-translational level. TBC treatment also reduces [³H]rosuvastatin accumulation in primary human hepatocytes. Quantitative comparison of post-translational modifications (PTMs) between TBC treatment and control showed concurrent increase in lysine acetylation at K675 (to 5.16 ± 2.7-fold of control) and decrease in dual phosphorylation at Ser659-Ser663 (to 0.34 ± 0.13-fold of control). A variant S659A-S663A-K675Q-OATP1B1 that mimics these concurrent PTM changes reduces OATP1B1-mediated transport compared with the wild-type control, supporting a role for altered PTMs in downregulation of OATP1B1 transport function upon KDAC6 loss-of-function. In addition, K49, a residue important in maintaining OATP1B1 transport function, was identified as acetylated for the first time. This study identifies KDAC6 as a key enzyme regulating lysine acetylation of OATP1B1 and maintaining OATP1B1 transport function, thereby implying a novel KDAC6-linked mechanism in OATP1B1-mediated drug-drug interactions. SIGNIFICANCE STATEMENT: This study identifies lysine deacetylase 6 (KDAC6) as a key enzyme involved in post-translational regulation of OATP1B1. Current findings demonstrate that KDAC6-dependent acetylation-phosphorylation axis modulates OATP1B1 transport function and provides a mechanistic basis by which altered KDAC6 activity may influence OATP1B1-mediated drug-drug interactions.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 7","pages":"100132"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13421777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387725","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":"Effects of ivermectin on the activation and desensitization of the human GABA_A receptor.","authors":"Spencer R Pierce, Allison L Germann, Ka Tak Tsoi, Gustav Akk","doi":"10.1016/j.molpha.2026.100134","DOIUrl":"10.1016/j.molpha.2026.100134","url":null,"abstract":"<p><p>Ivermectin (IVM) is a widely used antiparasitic drug that acts through allosteric activation and potentiation of the glutamate-gated chloride channel present in neurons and muscle cells of helminths and insects. In mammals, IVM activates several members of the Cys-loop ion channel family, including the GABA_A receptor. Although the centrally located GABA_A receptors are protected against the actions of IVM by the transporter protein P-glycoprotein 1 present in the blood-brain barrier, many peripheral GABA_A receptors are exposed to blood-borne IVM. Here, we have investigated the activating and modulatory effects of IVM on α5β3γ2L and α1β3γ2L GABA_A receptors expressed in Xenopus oocytes. We show that IVM is a potent and efficacious agonist of the α5β3γ2L receptor with an EC₅₀ of 0.06 μM and a maximal probability of being in the active state >0.3. IVM, unlike typical agonists of the GABA_A receptor, does not desensitize the receptor even in 20-minute-long applications. Receptors desensitized by high concentrations of GABA are reactivated upon exposure to IVM. Coapplication of IVM with GABA or the allosteric agonist, etomidate, manifests as simple additivity of individual responses rather than potentiation. The application of the allosteric agonist, pentobarbital, is without effect or reduces the response to IVM. Overall, GABA_A receptor activation by IVM exhibits a number of unique properties not encountered with commonly used or studied GABAergic drugs. SIGNIFICANCE STATEMENT: Peripheral GABA_A receptors are accessible to the widely used antiparasitic agent ivermectin (IVM). This study shows that IVM activates the α5β3γ2L and α1β3γ2L subtypes at therapeutic concentrations. Responses to IVM are not potentiated by the transmitter GABA or the allosteric agonists etomidate or pentobarbital. Receptors activated by IVM do not exhibit desensitization, while receptors desensitized by GABA are reactivated upon exposure to IVM.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 7","pages":"100134"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352512","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":"Binding affinities for histamine receptors 1 to 4: Systematic comparison of ligands from the Psychoactive Drug Screening Program K_i database and International Union of Basic and Clinical Pharmacology/British Pharmacological Society Guide to Pharmacology.","authors":"Lilly Josephine Bindel, Roland Seifert","doi":"10.1016/j.molpha.2026.100139","DOIUrl":"10.1016/j.molpha.2026.100139","url":null,"abstract":"<p><p>Histamine receptors (H₁R-H₄R) are G protein-coupled receptors with large physiological and therapeutic relevance. Despite extensive research, a systematic and cross-database overview of ligands is missing. This review integrates the Psychoactive Drug Screening Program (PDSP) K_i database and the International Union of Basic and Clinical Pharmacology/British Pharmacological Society (IUPHAR/BPS) Guide to Pharmacology, both having different scopes and curation principles, and evaluates concordance of H_xR ligands across databases and experimental systems. Binding affinities (K_i) for 302 ligands targeting recombinant human H_xR were extracted from the PDSP K_i database (accessed January 2026) and converted to pK_i. A total of 302 ligands with relevant binding affinities were identified, including approved drugs and experimental compounds. Functional annotations and further binding affinities were retrieved from the IUPHAR/BPS Guide to Pharmacology and complementary literature, revealing missing or incomplete functional characterization for 69 ligands. Although most ligands were selective for a single H_xR, others displayed multireceptor affinity. Cross-database comparisons found limited overlap in ligands, differences in primary literature, and pK_i deviations. Comparisons with native human tissues and nonhuman species demonstrated substantial variability, with deviations of up to pK_i 4.2 in human brain tissues and up to pK_i 3.2 across species. This database-driven analysis highlights strengths and limitations of the PDSP K_i database (broad data aggregation) and the IUPHAR/BPS Guide to Pharmacology (curated representative selection). Although together they provide extensive coverage of H_xR ligands, incomplete overlap and selective data inclusion limit direct comparability and may give the impression of missing data despite substantial experimental data. Systematic integration is essential to improve data reliability, summarize knowledge, and support future drug development. SIGNIFICANCE STATEMENT: This review provides a systematic overview of ligand binding affinities and functional profiles across all 4 H_xR. It integrates data from the PDSP K_i database and the IUPHAR/ BPS Guide to Pharmacology and compares recombinant human H_xR with native tissues and several species. Substantial data gaps, inconsistencies, and context-dependent variability are revealed. The PDSP K_i database has large potential for use in scientific research and in the support of drug development.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 7","pages":"100139"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13494103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376351","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":"Neuroprotective in vitro effects of histone deacetylase 6-selective inhibitor SW-100 toward oxaliplatin-derived toxicity.","authors":"Angelica Squarzoni, Arianna Scuteri, Elisabetta Donzelli, Virginia Rodriguez-Menendez, Guido Cavaletti","doi":"10.1016/j.molpha.2026.100137","DOIUrl":"10.1016/j.molpha.2026.100137","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy is a common side effect of chemotherapy drugs. Currently, no effective preventive strategies or treatments are available. In recent years, histone deacetylase inhibitors (HDACis), initially approved for hematologic malignancies, have been proposed for neuroprotective purposes. HDACis inhibit histone deacetylases, a group of enzymes involved in the regulation of both histone and nonhistone proteins. In this study, we tested the antitumorigenic abilities of 3 different HDACis (SAHA, romidepsin, and SW-100) in combination with oxaliplatin (OHP) in 3 colorectal cancer cell lines (HT-29, HCT-15, and Caco-2). OHP is the gold standard antineoplastic therapy for the treatment of colorectal cancer, and it is also known to induce peripheral neuropathy, which affects patients' quality of life. OHP treatment often forces a reduction of the clinical effective drug dose, or even an interruption in anticancer treatment. Therefore, we also assessed the efficacy of 3 HDACis in mitigating the neurotoxicity induced by OHP in E15 rat embryo dorsal root ganglia. Apoptotic and cell proliferation pathways were tested through immunoblot analysis, immunofluorescence, and cell survival analysis. The results of this study show that SW-100, a selective histone deacetylase 6 inhibitor, induces apoptosis and reduces cell viability in both HT-29 and HCT-15 when used in combination with OHP. Besides its antineoplastic activity, SW-100 can protect against OHP neurotoxicity, limiting the activation of caspase 3 and selectively inducing α-tubulin acetylation to possibly stabilize axonal transport. In conclusion, we propose SW-100 and OHP as a viable combination for future studies on the treatment of chemotherapy-induced peripheral neuropathy. SIGNIFICANCE STATEMENT: Chemotherapy-induced peripheral neuropathy is a common side effect of oxaliplatin, a drug used for the treatment of colorectal cancer. This study demonstrated that in vitro cotreatment with the histone deacetylase 6 selective inhibitor, SW-100, attenuates the neurotoxic effect of oxaliplatin while maintaining the efficacy of the treatment.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 7","pages":"100137"},"PeriodicalIF":3.0,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382376","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}