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Molecular Pharmacology

Maroua Jalouli, Sophie Mokas, Catherine A Turgeon, Laurent Lamalice, Darren E Richard
Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are an essential part for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC). AngII increases HIF-1 transcriptional activity by modulating specific signaling pathways. In VSMC, p42/p44 mitogen-activated protein kinase (MAPK) pathway activation is essential for HIF-1-mediated transcription during AngII treatment...
August 16, 2017: Molecular Pharmacology
Anastasios Chanalaris, Christine Doherty, Brian D Marsden, Gabriel Bambridge, Stephen P Wren, Hideaki Nagase, Linda Troeberg
Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3), through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1)...
August 10, 2017: Molecular Pharmacology
Daniel J Shin, Allison L Germann, Joseph H Steinbach, Gustav Akk
Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has found that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear...
August 8, 2017: Molecular Pharmacology
Muhammad Imran Sohail, Diethart Schmid, Katrin Wlcek, Matthias Spork, Gergely Szakacs, Michael Trauner, Thomas Stockner, Peter Chiba
The bile salt export pump (BSEP/ABCB11) transports bile salts from hepatocytes into bile canaliculi. Its malfunction is associated with severe liver disease. One reason for functional impairment of BSEP is systemic administration of drugs, which as a side effect inhibit the transporter. Therefore, drug candidates are routinely screened for potential interaction with this transporter. Hence understanding the functional biology of BSEP is of key importance. In this study we engineered the transporter in order to dissect interdomain communication paths...
August 7, 2017: Molecular Pharmacology
Hoa Tn Phan, Benita Sjogren, Richard R Neubig
RGS2 plays a significant role in alleviating vascular contraction and promoting vascular relaxation due to its GTPase accelerating protein (GAP) activity toward Gαq Mice lacking RGS2 display a hypertensive phenotype and several RGS2 missense mutations have been found predominantly in hypertensive human subjects. However, the mechanisms whereby these mutations could impact blood pressure is unknown. Here, we selected 16 rare, missense mutations in RGS2 identified in various human exome sequencing projects and evaluated their ability to inhibit intracellular calcium release mediated by the angiotensin II receptor type 1 (AT1R)...
August 7, 2017: Molecular Pharmacology
Emilia Kansanen, Suvi M Kuosmanen, Anna-Kaisa Ruotsalainen, Heidi Hynynen, Anna-Liisa Levonen
Nitro-fatty acids are reactive signaling mediators that are formed when unsaturated fatty acids react with nitric oxide or nitric oxide-derived species. Nitro-fatty acids can modify specific signaling pathways via post-translational modifications of cysteine residues in key regulatory proteins. One of the signaling cascades activated by nitro-fatty acids is the Keap1-Nrf2 pathway. We have previously studied the effects of nitro-oleic acid (OA-NO2) on the human endothelial cell transcriptome. We observed that endothelin receptor B (ET-B, EDNRB), the receptor mediating the vasodilatory effects of endothelin-1 (ET-1) is induced by OA-NO2 Inasmuch as ET-1 is one of the key regulators of vascular tone, we chose to examine in more detail the effect of OA-NO2 on endothelin signaling in human endothelial cells...
August 4, 2017: Molecular Pharmacology
Brandon M Brown, Heesung Shim, Miao Zhang, Vladimir Yarov-Yarovoy, Heike Wulff
Small-conductance (KCa2) and intermediate-conductance (KCa3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin mediated gating mechanism. Most existing positive gating modulators like EBIO, NS309 or SKA-31 activate both channels with similar potencies. We previously performed a structure activity relationship study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 towards KCa3.1 selectivity and identified SKA-121 (5-methylnaphtho[2,1-d]oxazol-2-amine), which displays 40-fold selectivity for KCa3...
July 31, 2017: Molecular Pharmacology
Andrea Martella, Huub Sijben, Arne Rufer, Juergen Fingerle, Uwe Grether, Christoph Ullmer, Thomas Hartung, Ad IJzerman, Mario van der Stelt, Laura Heitman
The endocannabinoid system (ECS) and in particular the cannabinoid receptor 2 (CB2R), raised the interest of many medicinal chemistry programs for its therapeutic relevance in several (patho)physiological processes. However, the the physico-chemical properties of tool compounds for CB2R (e.g. the radioligand [(3)H]CP55,940) are not optimal, despite the research efforts in developing effective drugs to target this system. At the same time, the importance of drug-target binding kinetics is growing, as the kinetic binding profile of a ligand may provide important insights for the resulting in vivo efficacy...
July 26, 2017: Molecular Pharmacology
Zhihui Zheng, Zanmei Zhao, Shuqiang Li, Xinhua Lu, Mengxi Jiang, Jie Lin, Yunqi An, Yang Xie, Meishu Xu, Wenbin Shen, Grace Guo, YIxian Huang, Song Li, Xuexia Zhang, Wen Xie
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose and lipids. FXR agonists have shown promise for the treatment of NAFLD. Here we report Altenusin (2076A), a natural non-steroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3...
July 24, 2017: Molecular Pharmacology
Daiki Okuhara, Shogo Furutani, Katsuhiko Ito, Makoto Ihara Ihara, Kazuhiko Matsuda
The pH-sensitive chloride channels (pHCls) are broadly expressed in insects, but little is known about their physiological role, diversity and sensitivity to insecticides acting on relevant chloride channels. Here we have sequenced 50 transcripts of the pHCl-1 gene from the brain, third thoracic ganglion (T3G) and midgut of larvae of silkworm Bombyx mori. It was found that >50 variants were expressed with distinct splicing in the T3G compared to the brain and midgut. Of the variants detected, variant 9, which was expressed most abundantly in the larvae, was reconstituted in Xenopus laevis oocytes to characterise its pH- and ivermectin sensitivity...
July 24, 2017: Molecular Pharmacology
Alison Gardner, Wei Wu, Steven Thomson, Eva-Maria Zangerl-Plessl, Anna Stary-Weinzinger, Michael Sanguinetti
Outward current conducted by human ether-a-g-go-related gene type 1 (hERG1) channels is a major determinant of action potential repolarization in the human ventricle. Ginsenoside 20(S)-Rg3 (Rg3), an alkaloid isolated from the root of Panax ginseng slows the rate of hERG1 deactivation, induces channels to open at more negative potentials than normal and increases current magnitude. The onset of Rg3 action is extremely fast, suggesting that it binds to an extracellular accessible site on the channel to alter its gating...
July 13, 2017: Molecular Pharmacology
Narae Lee, Sua Jeong, Kang-Chang Kim, Jin-Ah Kim, Jin-Yong Park, Ho-Won Kang, Edward Perez-Reyes, Jung-Ha Lee
Calcium-dependent inactivation of high voltage-activated Ca(2+) channels plays a crucial role in limiting rises in intracellular calcium (Ca(2+)i). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming α subunit. In contrast, little is known about how Ca(2+)i can regulate low voltage-activated T-type Ca(2+) channels. Using whole cell patch clamp, we examined the biophysical properties of Ca(2+) current through the three T-type Ca(2+) channel isoforms, Cav3...
September 2017: Molecular Pharmacology
Terry P Kenakin
An index of agonism is described which can be used to quantify agonist receptor selectivity, bias, cell-based agonism and the effects of receptor mutation on signaling . The parameter is derived from agonist concentration-response curves and is comprised of the maximal response to the agonist (max) and the EC50 (concentration of agonist producing half maximal response) in the form of ΔLog(max/EC50). This parameter is derived from equations describing agonists as positive allosteric facilitators of receptor-signaling protein interaction...
July 5, 2017: Molecular Pharmacology
Ximing Xu, Cecile Mathieu, Jeremy Berthelet, Romain Duval, Linh Chi Bui, Florent Busi, Jean-Marie Dupret, Fernando Rodrigues-Lima
Thiram (tetramethylthiuram disulfide) is a representative dithiocarbamate (DTC) pesticide used in both the field and as a seed protectant. The widespread use of Thiram and other DTC pesticides has raised concerns for health as these compounds can exert neuropathic, endocrine disruptive and carcinogenic effects. These toxic effects are thought to rely, at least in part, on the reaction of Thiram (and certain of its metabolites) with cellular protein thiols with subsequent loss of protein function. So far, a limited number of molecular targets of Thiram have been reported including few enzymes such as dopamine β-hydroxylase, 11β-hydroxysteroid dehydrogenase and brain glycogen phosphorylase...
July 3, 2017: Molecular Pharmacology
Yanhua Wang, Lirong Jiang, Xi Mo, Yu Lan, Xiao Yang, Xinyi Liu, Jian Zhang, Li Zhu, Junling Liu, Xiaolin Wu
Smad4, a key transcription factor in the TGF-β signaling pathway, is involved in a variety of cell physiological and pathological processes. Here, we characterized megakaryocyte/platelet-specific Smad4 deficiency in mice to elucidate its effect on platelet function. We found that megakaryocyte/platelet-specific loss of Smad4 caused mild thrombocytopenia and significantly extended first occlusion time and tail bleeding time in mice. Smad4-deficient platelets showed reduced agonist-induced platelet aggregation...
June 29, 2017: Molecular Pharmacology
Dhwanil A Dalwadi, John A Schetz
The α-like octopamine receptors are believed to be the evolutionary precursor to the vertebrate α2-adrenergic receptors (α2-ARs) based upon sequence similarity and the ability to interact with norepinephrine and a number of compounds that bind with high affinity to α2-ARs. Barnacles and fruit flies are two prominent model marine and terrestrial representatives of the Arthropoda phylum, and while α-like OctRs have been cloned from Balanus improvisus (BiOctR) and Drosophila melanogaster (DmOctR), little is known about the structure-activity space for these important species...
June 29, 2017: Molecular Pharmacology
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick Pieschl, Debra Post-Munson, John Watson, David R Langley, Michael Ahlijanian, Linda Bristow, James Herrington
NaV1.7 is genetically implicated in human pain perception. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations result in congenital insensitivity to pain (CIP). Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a templated target strategy approach employing chimeras with the bacterial channel, NavAb...
June 23, 2017: Molecular Pharmacology
Shaolan Wang, Xinya Xie, Ting Lei, Kang Zhang, Baochang Lai, Zihui Zhang, Youfei Guan, Guangmei Mao, Lei Xiao, Nanping Wang
Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and qRT-PCR showed that oxidized-LDL (oxLDL) or tumor necrosis factor alpha (TNFα) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of oxLDL or TNFα...
May 25, 2017: Molecular Pharmacology
Zijian Li
A receptor is a protein molecule that receives chemical signals from outside a cell, which enables the cell to respond to the signal molecule. Receptors mediate numerous important physiologic effects upon binding extracellular agonists. However, sustained activation of the receptor may lead to pathologic effects. Cells can regulate the number and function of receptors to alter their sensitivity to different molecules by a feedback mechanism, such as change in the receptor conformation, uncoupling of the receptor effector molecules, receptor sequestration, etc...
September 2017: Molecular Pharmacology
Kristen E DeDominicis, Niaz Sahibzada, Thao T Olson, Yingxian Xiao, Barry B Wolfe, Kenneth J Kellar, Robert P Yasuda
The α4β2 nicotinic acetylcholine receptor (nAChR) is important in central nervous system physiology and in mediating several of the pharmacological effects of nicotine on cognition, attention, and affective states. It is also the likely receptor that mediates nicotine addiction. This receptor assembles in two distinct stoichiometries: (α4)2(β2)3 and (α4)3(β2)2, which are referred to as high-sensitivity (HS) and low-sensitivity (LS) nAChRs, respectively, based on a difference in the potency of acetylcholine to activate them...
September 2017: Molecular Pharmacology
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