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The M3 muscarinic acetylcholine receptor can signal through multiple G protein families Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-19 Jeffrey S Smith, Ari S Hilibrand, Meredith A Skiba, Andrew N Dates, Victor G Calvillo-Miranda, Andrew C. Kruse
The M3 muscarinic acetylcholine receptor (M3R) is a G protein coupled receptor (GPCR) that regulates important physiological processes including vascular tone, bronchoconstriction, and insulin secretion. It is expressed on a wide variety of cell types, including pancreatic beta, smooth muscle, neuronal, and immune cells. Agonist binding to the M3R is thought to initiate intracellular signaling events
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Development of a Novel Assay for Direct Assessment of Selective Amylin Receptor Activation Reveals Novel Differences in Behavior of Selective and Nonselective Peptide Agonists Mol. Pharmacol. (IF 3.6) Pub Date : 2024-05-01 Peter Keov, George Christopoulos, Caroline A. Hick, Tine Glendorf, Borja Ballarín-González, Denise Wootten, Patrick M. Sexton
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Therapeutic Potential for Metabotropic Glutamate Receptor 7 Modulators in Cognitive Disorders Mol. Pharmacol. (IF 3.6) Pub Date : 2024-05-01 Harrison H. Parent, Colleen M. Niswender
Metabotropic glutamate receptor 7 (mGlu7) is the most highly conserved and abundantly expressed mGlu receptor in the human brain. The presynaptic localization of mGlu7, coupled with its low affinity for its endogenous agonist, glutamate, are features that contribute to the receptor’s role in modulating neuronal excitation and inhibition patterns, including long-term potentiation, in various brain regions
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2023 Julius Axelrod Symposium: Plant-Derived Molecules Acting on G Protein-Coupled Receptors Mol. Pharmacol. (IF 3.6) Pub Date : 2024-05-01 Nedjma Labani, Florence Gbahou, Shuangyu Lian, Jianfeng Liu, Ralf Jockers
Plant extracts have played a significant role in traditional medicine for centuries, contributing to improved health and the treatment of various human illnesses. G protein-coupled receptors (GPCRs) are crucial in numerous physiologic functions, and there is growing evidence suggesting their involvement in the therapeutic effects of many plant extracts. In recent years, scientists have identified an
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A Conversation with ChatGPT on Contentious Issues in Senescence and Cancer Research Mol. Pharmacol. (IF 3.6) Pub Date : 2024-05-01 Ahmed M. Elshazly, Uruk Shahin, Sofian Al Shboul, David A. Gewirtz, Tareq Saleh
Artificial intelligence (AI) platforms, such as Generative Pretrained Transformer (ChatGPT), have achieved a high degree of popularity within the scientific community due to their utility in providing evidence-based reviews of the literature. However, the accuracy and reliability of the information output and the ability to provide critical analysis of the literature, especially with respect to highly
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Deorphanization of G Protein Coupled Receptors (GPCRs): a historical perspective. Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-15 Luca Franchini, Cesare Orlandi
Counting over 800 members, G Protein Coupled Receptors (GPCRs) form the largest family of membrane receptors encoded in the human genome. Since the discovery of G proteins and GPCRs in the late 1970s and early 1980s, a significant portion of the GPCR research has been focused on identifying ligand/receptor pairs in parallel to studies related to their signaling properties. Despite significant advancements
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Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-05 King Clyde B. Yabut, Alice Martynova, Abhinav Nath, Benjamin P Zercher, Matthew F. Bush, Nina Isoherranen
Liver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and up to two fatty acids can bind to FABP1 simultaneously
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Pharmacological Characterization and Radiolabeling of VUF15485, a High-Affinity Small-Molecule Agonist for the Atypical Chemokine Receptor ACKR3 Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-01 Aurelien M. Zarca, Ilze Adlere, Cristina P. Viciano, Marta Arimont-Segura, Max Meyrath, Icaro A. Simon, Jan Paul Bebelman, Dennis Laan, Hans G. J. Custers, Elwin Janssen, Kobus L. Versteegh, Maurice C. M. L. Buzink, Desislava N. Nesheva, Reggie Bosma, Iwan J. P. de Esch, Henry F. Vischer, Maikel Wijtmans, Martyna Szpakowska, Andy Chevigné, Carsten Hoffmann, Chris de Graaf, Barbara A. Zarzycka, Albert
Atypical chemokine receptor 3 (ACKR3), formerly referred to as CXCR7, is considered to be an interesting drug target. In this study, we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new ACKR3 small-molecule agonist, that will serve as an important new tool to study this β-arrestin-biased chemokine receptor. VUF15485 binds with nanomolar affinity (pIC50 =
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Prodigiosin Inhibits Transforming Growth FactorβSignaling by Interfering Receptor Recycling and Subcellular Translocation in Epithelial Cells Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-01 Shun-Ban Tai, Chih-yin Huang, Chih-Ling Chung, Ping-Jyun Sung, Zhi-Hong Wen, Chun-Lin Chen
Prodigiosin (PG) is a naturally occurring polypyrrole red pigment produced by numerous microorganisms including some Serratia and Streptomyces strains. PG has exhibited promising anticancer activity; however, the molecular mechanisms of action of PG on malignant cells remain ambiguous. Transforming growth factor-β (TGF-β) is a multifunctional cytokine that governs a wide array of cellular processes
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RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine Mol. Pharmacol. (IF 3.6) Pub Date : 2024-04-01 Vasiliki Mitsi, Anne Ruiz, Claire Polizu, Zahra Farzinpour, Aarthi Ramakrishnan, Randal A. Serafini, Eric M. Parise, Madeline Floodstrand, Omar K. Sial, Sevasti Gaspari, Cheuk Y. Tang, Eric J. Nestler, Eric F. Schmidt, Li Shen, Venetia Zachariou
The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiologic and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting versus fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we
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2023 Julius Axelrod Symposium: Plant-derived molecules acting on GPCRs Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-08 Labani, N., Gbahou, F., Lian, S., Liu, J., Jockers, R.
Plant extracts have played a significant role in traditional medicine for centuries, contributing to improved health and the treatment of various human illnesses. G protein-coupled receptors (GPCRs) are crucial in numerous physiological functions, and there is growing evidence suggesting their involvement in the therapeutic effects of many plant extracts. In recent years, scientists have identified
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Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Nayara Braga Emidio, Brandi M. Small, Amanda R. Keller, Ross W. Cheloha, Laura M. Wingler
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Coexpressedδ-,μ-, andκ-Opioid Receptors Modulate Voltage-Gated Ca2+Channels in Gastric-Projecting Vagal Afferent Neurons Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Hannah J. Goudsward, Victor Ruiz-Velasco, Salvatore L. Stella, Lisa B. Willing, Gregory M. Holmes
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Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-15 Gilchrist, J. M., Yang, N.-D., Jiang, V., Moyer, B. D.
Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (NaVs) are responsible for action potential initiation and transmission of pain signals. NaV1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective
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Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Chenxia Yang, Qinqin Li, Fang Hu, Yani Liu, KeWei Wang
The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used
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Extrahelical Binding Site for a 1H-Imidazo[4,5-c]quinolin-4-amine A3Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7 Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Courtney L. Fisher, Matteo Pavan, Veronica Salmaso, Robert F. Keyes, Tina C. Wan, Balaram Pradhan, Zhan-Guo Gao, Brian C. Smith, Kenneth A. Jacobson, John A. Auchampach
This study describes the localization and computational prediction of a binding site for the A3 adenosine receptor (A3AR) positive allosteric modulator 2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H)
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Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KATPChannels Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Kangjun Li, Samantha J. McClenahan, Changho Han, Joseph D. Bungard, Upendra Rathnayake, Olivier Boutaud, Joshua A. Bauer, Emily L. Days, Craig W. Lindsley, Elaine L. Shelton, Jerod S. Denton
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ent-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Casq2-/- Mice Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-15 Gochman, A., Do, T. Q., Kim, K., Schwarz, J. A., Thorpe, M. P., Blackwell, D. J., Ritschel, P. A., Smith, A. N., Rebbeck, R. T., Akers, W. S., Cornea, R. L., Laver, D. R., Johnston, J. N., Knollmann, B. C.
Intracellular Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined
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Circadian Regulation of Endocrine Fibroblast Growth Factors on Systemic Energy Metabolism Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Zhenning Yang, Helmut Zarbl, Grace L. Guo
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Drug Targeting of Acyltransferases in the Triacylglyceride and 1-O-AcylCeramide Biosynthetic Pathways Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Maria Hernandez-Corbacho, Daniel Canals
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Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress–Associated Immunogenic Cell Death in Cancer? Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Jeremy A. Hengst, Asvelt J. Nduwumwami, Arati Sharma, Jong K. Yun
The three arms of the unfolded protein response (UPR) surveil the luminal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and are
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A Brief Overview of the Toxic Sphingomyelinase Ds of Brown Recluse Spider Venom and Other Organisms and Simple Methods To Detect Production of Its Signature Cyclic Ceramide Phosphate Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-15 Lachmayr, H., Merrill, A. H.
A special category of phospholipase D (PLD) in the venom of the brown recluse spider (Loxosceles reclusa) and several other sicariid spiders accounts for the dermonecrosis and many of the other clinical symptoms of envenomation. Related proteins are produced by other organisms, including fungi and bacteria. These PLDs are often referred to as sphingomyelinase Ds (SMase Ds) because they cleave sphingomyelin
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Expression of Ceramide Synthases in Mice and Their Roles in Regulating Acyl-Chain Sphingolipids: A Framework for Baseline Levels and Future Implications in Aging and Disease Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Whitney J. Richardson, Sophia B. Humphrey, Sophia M. Sears, Nicholas A. Hoffman, Andrew J. Orwick, Mark A. Doll, Chelsea L. Doll, Catherine Xia, Maria Hernandez-Corbacho, Justin M. Snider, Lina M. Obeid, Yusuf A. Hannun, Ashley J. Snider, Leah J. Siskind
Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1–6), each with a preference for different fatty acyl chain lengths
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Development of an LC-MS/MS Method to Measure Sphingolipids in CSF from Patients with Multiple Sclerosis Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Yadira X. Perez-Paramo, Dawn Dufield, Rathna Veeramachaneni, Emily Parkhurst, Christopher Harp, Akshaya Ramesh, Ryan C. Winger, Anne H. Cross, Jeffrey M. Gelfand, Amit Bar-Or, W. Rodney Mathews, Veronica G. Anania
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Perspective: Therapeutic Implications for Sphingolipids in Health and Disease Mol. Pharmacol. (IF 3.6) Pub Date : 2024-03-01 Christopher J. Clarke, Ashley J. Snider
Long thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, including lysosomal storage disorders, multiple sclerosis, inflammation, and cancer as well as metabolic syndrome and obesity. In addition, the indications
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RGS4 actions in mouse prefrontal cortex modulate behavioral and transcriptomic responses to chronic stress and ketamine Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-13 Mitsi, V., Ruiz, A., Polizu, C., Farzinpour, Z., Ramakrishnan, A., Serafini, R. A., Parise, E. M., Floodstrand, M., Sial, O. K., Gaspari, S., Tang, C. Y., Nestler, E. J., Schmidt, E. F., Shen, L., Zachariou, V.
The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiological and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting vs fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we demonstrate
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ent-Verticilide B1 inhibits type 2 ryanodine receptor channels and is antiarrhythmic in Casq2-/- mice Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-22 Aaron Gochman, Tri Q Do, Kyungsoo Kim, Jacob A Schwarz, Madelaine P Thorpe, Daniel J Blackwell, Paxton Ritschel, Abigail N Smith, Robyn T Rebbeck, Wendell S Akers, Razvan L Cornea, Derek R. Laver, Jeffrey N Johnston, Bjorn C Knollmann
Ca2+ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca2+ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor ent-(+)-verticilide (ent-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (nat-(-)-verticilide). Here, we examined its 18-membered
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Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-09 John M. Gilchrist, Nien-Du Yang, Victoria Jiang, Bryan D. Moyer
Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (NaVs) are responsible for action potential initiation and transmission of pain signals. NaV1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective
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Signaling Specificity and Kinetics of the Human Metabotropic Glutamate Receptors Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-01 Tyler W. McCullock, Loren P. Cardani, Paul J. Kammermeier
Metabotropic glutamate receptors (mGluRs) are obligate dimer G protein coupled receptors that can all function as homodimers. Here, each mGluR homodimer was examined for its G protein coupling profile using a bioluminescence resonance energy transfer-based assay that detects the interaction between a split YFP-tagged Gβ1γ2 and a Nanoluciferase tagged free Gβγ sensor, MAS-GRK3-ct- nanoluciferase with
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A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-01 Justin J. Kim, Ilse K. Schaeffner, David E. Heppner, Ciric To, Pasi A. Jänne, Tyler S. Beyett, Michael J. Eck
Lung cancer is commonly caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric kinase inhibitors are unaffected by common ATP-site resistance mutations and represent a promising therapeutic strategy for targeting drug-resistant EGFR variants. However, allosteric inhibitors are antagonized by kinase dimerization, and understanding this phenomenon has been limited to
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Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H1Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-01 Daniel A. McNaught-Flores, Albert J. Kooistra, Yu-Chia Chen, Jose-Antonio Arias-Montano, Pertti Panula, Rob Leurs
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β-Caryophyllene Inhibits Monoacylglycerol Lipase Activity and Increases 2-Arachidonoyl Glycerol Levels In Vivo: A New Mechanism of Endocannabinoid-Mediated Analgesia? Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-01 Jost Klawitter, Wiebke Weissenborn, Iuliia Gvon, Mackenzie Walz, Jelena Klawitter, Matthew Jackson, Cristina Sempio, Sonja L. Joksimovic, Touraj Shokati, Ingo Just, Uwe Christians, Slobodan M. Todorovic
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Pharmacological Targeting of Senescence with Senolytics as a New Therapeutic Strategy for Neurodegeneration Mol. Pharmacol. (IF 3.6) Pub Date : 2024-02-01 Miriam Richardson, Des R. Richardson
Cellular senescence is a state of permanent cell-cycle arrest. Early in life, senescence has a physiologic role in tumor suppression and wound healing. However, gradually, as these senescent cells accumulate over the lifespan of an organism, they contribute to inflammation and the progression of age-related diseases, including neurodegeneration. Targeting senescent cells using a class of drugs known
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Extrahelical binding site for a 1H-imidazo[4,5-c]quinolin-4-amine A3 adenosine receptor positive allosteric modulator on helix 8 and distal portions of transmembrane domains 1 and 7 Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-05 Fisher, C. L., Pavan, M., Salmaso, V., Keyes, R. F., Wan, T. C., Pradhan, B., Gao, Z.-G., Smith, B. C., Jacobson, K. A., Auchampach, J. A.
This study describes the localization and computational prediction of a putative binding site of an A3 adenosine receptor (A3AR) positive allosteric modulator LUF6000 (2-cyclohexyl-1H-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix
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FANNING THE FLAMES OF ER STRESS: Can sphingolipid metabolism be targeted to enhance ER stress associated immunogenic cell death in cancer? Mol. Pharmacol. (IF 3.6) Pub Date : 2023-12-21 Hengst, J. A., Nduwumwami, A. J., Sharma, A., Yun, J. K.
The three arms of the unfolded protein response (UPR) surveil the lumenal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and modulators
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A19F-qNMR-Guided Mathematical Model for G Protein-Coupled Receptor Signaling Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-01 Jesús Giraldo, Jesper J. Madsen, Xudong Wang, Lei Wang, Cheng Zhang, Libin Ye
G protein-coupled receptors (GPCRs) exhibit a wide range of pharmacological efficacies, yet the molecular mechanisms responsible for the differential efficacies in response to various ligands remain poorly understood. This lack of understanding has hindered the development of a solid foundation for establishing a mathematical model for signaling efficacy. However, recent progress has been made in delineating
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Dual-Activity Fluoroquinolone-Transportan 10 Conjugates Offer Alternative Leukemia Therapy during Hematopoietic Cell Transplantation Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-01 Jan Jakub Lica, Mateusz Heldt, Milosz Wieczór, Pawel Chodnicki, Natalia Ptaszyńska, Natalia Maciejewska, Anna Łęgowska, Wioletta Brankiewicz, Katarzyna Gucwa, Anna Stupak, Bhaskar Pradhan, Agata Gitlin-Domagalska, Dawid Dębowski, Sławomir Milewski, Maria Bieniaszewska, Grzegorz Jan Grabe, Andrzej Hellmann, Krzysztof Rolka
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Synergy between Interleukin-1β, Interferon-γ, and Glucocorticoids to Induce TLR2 Expression Involves NF-κB, STAT1, and the Glucocorticoid Receptor Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-01 Akanksha Bansal, Cora Kooi, Keerthana Kalyanaraman, Sachman Gill, Andrew Thorne, Priyanka Chandramohan, Amandah Necker-Brown, Mahmoud M. Mostafa, Arya Milani, Richard Leigh, Robert Newton
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St. John’s Wort Formulations Induce Rat CYP3A23-3A1 Independent of Their Hyperforin Content Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-01 Anima M. Schäfer, Marta A. Rysz, Julia Schädeli, Michelle Hübscher, Haleh Khosravi, Michelle Fehr, Isabell Seibert, Olivier Potterat, Martin Smieško, Henriette E. Meyer zu Schwabedissen
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Passive Immunotherapies Targeting Amyloid-βin Alzheimer’s Disease: A Quantitative Systems Pharmacology Perspective Mol. Pharmacol. (IF 3.6) Pub Date : 2024-01-01 Milica Marković, Jelica Milošević, Weirong Wang, Yanguang Cao
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting Aβ have shown promise for AD treatment. Indeed, recent US Food and Drug Administration approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades
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Screening for Novel Type 2 Ryanodine Receptor Inhibitors by Endoplasmic Reticulum Ca2+Monitoring Mol. Pharmacol. (IF 3.6) Pub Date : 2023-12-01 Mai Takenaka, Masami Kodama, Takashi Murayama, Mari Ishigami-Yuasa, Shuichi Mori, Ryosuke Ishida, Junji Suzuki, Kazunori Kanemaru, Masami Sugihara, Masamitsu Iino, Aya Miura, Hajime Nishio, Sachio Morimoto, Hiroyuki Kagechika, Takashi Sakurai, Nagomi Kurebayashi
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Substituted Cysteine Modification and Protection with n-Alkyl-MTS Reagents Quantifies Steric Changes Induced by a Mutation in Anesthetic Binding Sites on GABA Type A Receptors Mol. Pharmacol. (IF 3.6) Pub Date : 2023-12-01 Kieran Bhave, Stuart A. Forman
Multiple approaches, including cryogenic electron microscopy (cryo-EM), indicate that the anesthetics etomidate and propofol modulate α1β2/3γ2 GABAA receptors by binding in overlapping transmembrane inter-subunit sites near βM286 and αL232 sidechains. High-precision approaches in functional receptors are needed for comparisons with cryo-EM. We previously used substituted cysteine modification and protection
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Molecular Mechanisms of Organic Anion Transporting Polypeptide–Mediated Organic Anion Clearance at the Blood–Cerebrospinal Fluid Barrier Mol. Pharmacol. (IF 3.6) Pub Date : 2023-12-01 Austin Sun, Bruno Hagenbuch, Edward J. Kelly, Joanne Wang
The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus epithelial (CPE) cells, plays an active role in removing drugs and metabolic wastes from the brain. Recent functional studies in isolated mouse choroid plexus (CP) tissues suggested the presence of organic anion transporting polypeptides (OATPs, encoded by SLCOs) at the apical membrane of BCSFB, which may clear large organic
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Targeting Cyclophilin A and CD147 to Inhibit Replication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and SARS-CoV-2-Induced Inflammation Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-15 Yang, F., Liu, C., Li, P., Wu, A., Ma-Lauer, Y., Zhang, H., Su, Z., Lu, W., von Brunn, A., Zhu, D.
Identification and development of effective therapeutics for coronavirus disease 2019 (COVID-19) are still urgently needed. The CD147-spike interaction is involved in the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 invasion process in addition to angiotensin-converting enzyme 2 (ACE2). Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection
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Passive Immunotherapies Targeting Amyloid-{beta} in Alzheimer's Disease: A Quantitative Systems Pharmacology Perspective Mol. Pharmacol. (IF 3.6) Pub Date : 2023-10-31 Markovic, M., Milosevic, J., Wang, W., Cao, Y.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) protein accumulation in the brain. Passive immunotherapies using monoclonal antibodies for targeting Aβ have shown promise for AD treatment. Indeed, recent US FDA approval of aducanumab and lecanemab, alongside positive donanemab Phase III results demonstrated clinical efficacy after decades of failed clinical
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Targeting Cyclophilin A and CD147 to Inhibit Replication of SARS-CoV-2 and SARS-CoV-2-Induced Inflammation Mol. Pharmacol. (IF 3.6) Pub Date : 2023-10-12 Fan Yang, Chenglong Liu, Pengyuan Li, Aihua Wu, Yue Ma-Lauer, Hao Zhang, Zhuang Su, Wei Lu, Albrecht von Brunn, Di Zhu
Identification and development of effective therapeutics for COVID-19 are still urgently needed. The CD147/Spike interaction is involved in the SARS-CoV-2 invasion process, in addition to ACE2. Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as Cyclosporine
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GαProtein Signaling Bias at Serotonin 1A Receptor Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-01 Rana Alabdali, Luca Franchini, Cesare Orlandi
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Gossypetin Prevents the Progression of Nonalcoholic Steatohepatitis by Regulating Oxidative Stress and AMP-Activated Protein Kinase Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-01 Eunji Oh, Jae Lee, Sungji Cho, Sung Wook Kim, Kyung Won, Won Sik Shin, Seung Hee Gwak, Joohun Ha, So Yeon Jeon, Jin-Hyang Park, Im-Sook Song, Themis Thoudam, In-Kyu Lee, Seonyong Kim, Se-Young Choi, Kyong-Tai Kim
Nonalcoholic steatohepatitis (NASH) is a severe liver metabolic disorder, however, there are still no effective and safe drugs for its treatment. Previous clinical trials used various therapeutic approaches to target individual pathologic mechanisms, but these approaches were unsuccessful because of the complex pathologic causes of NASH. Combinatory therapy in which two or more drugs are administered
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Amyloid-Beta Peptides 40 and 42 Employ Distinct Molecular Pathways for Cell Entry and Intracellular Transit at the Blood–Brain Barrier Endothelium Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-01 Zengtao Wang, Nidhi Sharda, Rajesh S. Omtri, Ling Li, Karunya K. Kandimalla
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Development of a Selective and High Affinity Radioligand, [3H]VU6013720, for the M4Muscarinic Receptor Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-01 Aidong Qi, Haley E. Kling, Natasha Billard, Alice L. Rodriguez, Li Peng, Jonathan W. Dickerson, Julie L. Engers, Aaron M. Bender, Mark S. Moehle, Craig W. Lindsley, Jerri M. Rook, Colleen M. Niswender
M4 muscarinic receptors are highly expressed in the striatum and cortex, brain regions that are involved in diseases such as Parkinson’s disease, schizophrenia, and dystonia. Despite potential therapeutic advantages of specifically targeting the M4 receptor, it has been historically challenging to develop highly selective ligands, resulting in undesired off-target activity at other members of the muscarinic
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Thermogenic Modulation of Adipose Depots: A Perspective on Possible Therapeutic Intervention with Early Cardiorenal Complications of Metabolic Impairment Mol. Pharmacol. (IF 3.6) Pub Date : 2023-11-01 Ahmed F. El-Yazbi, Mohamed A. Elrewiny, Hosam M. Habib, Ali H. Eid, Perihan A. Elzahhar, Ahmed S.F. Belal
Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic
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A brief overview of the toxic sphingomyelinase Ds of brown recluse spider venom and other organisms, and simple methods to detect production of its signature cyclic ceramide phosphate Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-22 Hannah Lachmayr, Alfred H Merrill
A special category of phospholipase Ds (PLD) in the venom of the brown recluse spider (Loxosceles reclusa) and several other Sicariid spiders accounts for the dermonecrosis and many of the other clinical symptoms of envenomation. Related proteins are produced by other organisms including fungi and bacteria. These PLDs are often referred to as sphingomyelinase Ds (SMase D) because they cleave sphingomyelin
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Atypical Chemokine Receptor 3 "Senses" CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-14 Schafer, C. T., Chen, Q., Tesmer, J. J. G., Handel, T. M.
Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging process restricts the availability of the chemokine agonist CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms
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Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-14 Campagna, N., Wall, E., Lee, K., Guo, J., Li, W., Yang, T., Baranchuk, A., El-Diasty, M., Zhang, S.
The human ether-a-go-go-related gene (hERG) encodes for the pore-forming subunit of the channel that conducts the rapidly activating delayed K+ current (IKr) in the heart. The hERG channel is important for cardiac repolarization, and reduction of its expression in the plasma membrane due to mutations causes long QT syndrome type 2 (LQT2). As such, promoting hERG membrane expression is a strategy to
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Induced Fit Describes Ligand Binding to Membrane-Associated Cytochrome P450 3A4 Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-14 Sweeney, D. T., Zarate-Perez, F., Stokowa-Sołtys, K., Hackett, J. C.
Cytochrome P450 3A4 (CYP3A4) is the dominant P450 involved in human xenobiotic metabolism. Competition for CYP3A4 therefore underlies several adverse drug–drug interactions. Despite its clinical significance, the mechanisms CYP3A4 uses to bind diverse ligands remain poorly understood. Highly monodisperse CYP3A4 embedded in anionic lipoprotein nanodiscs containing an equal mixture of 1-palmitoyl-2-
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Englerin A Inhibits T-Type Voltage-Gated Calcium Channels at Low Micromolar Concentrations Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-14 Wardas, B., Schneider, J. G., Klugbauer, N., Flockerzi, V., Beck, A.
Englerin A (EA) is a potent agonist of tetrameric transient receptor potential canonical (TRPC) ion channels containing TRPC4 and TRPC5 subunits. TRPC proteins form cation channels that are activated by plasma membrane receptors. They convert extracellular signals such as angiotensin II into cellular responses, whereupon Na+ and Ca2+ influx and depolarization of the plasma membrane occur. Via depolarization
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Licochalcone Mediates the Pain Relief by Targeting the Voltage-Gated Sodium Channel Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-14 Zhao, Q., Zhang, X., Long, S., Wang, S., Yu, H., Zhou, Y., Li, Y., Xue, L., Hu, Y., Yin, S.
Licorice is a traditional Chinese medicine and recorded to have pain relief effects in national pharmacopoeia, but the mechanisms behind these effects have not been fully explored. Among the hundreds of compounds in licorice, licochalcone A (LCA) and licochalcone B (LCB) are two important components belonging to the chalcone family. In this study, we compared the analgesic effects of these two licochalcones
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Screening for novel RyR2 inhibitors by ER Ca2+ monitoring Mol. Pharmacol. (IF 3.6) Pub Date : 2023-09-07 Takenaka, M., Kodama, M., Murayama, T., Ishigami-Yuasa, M., Mori, S., Ishida, R., Suzuki, J., Kanemaru, K., Sugihara, M., Iino, M., Miura, A., Nishio, H., Morimoto, S., Kagechika, H., Sakurai, T., Kurebayashi, N.
Type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic/sarcoplasmic reticulum (ER/SR) that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and heart failure, where spontaneous Ca2+ release via hyperactivated RyR2
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Molecular Mechanisms of OATP/SLCO-mediated Organic Anion Clearance at the Blood-Cerebrospinal Fluid Barrier Mol. Pharmacol. (IF 3.6) Pub Date : 2023-08-31 Sun, A., Hagenbuch, B., Kelly, E. J., Wang, J.
The blood-cerebrospinal fluid barrier (BCSFB), formed by the choroid plexus epithelial (CPE) cells, plays an active role in removing drugs and metabolic wastes from the brain. Recent functional studies in isolated mouse choroid plexus (CP) tissues suggested the existence of organic anion transporting polypeptides (OATPs, encoded by SLCOs) at the apical membrane of BCSFB, which may clear large organic
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