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Molecular Pharmacology

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https://www.readbyqxmd.com/read/28705808/molecular-basis-of-altered-herg1-channel-gating-induced-by-ginsenoside-rg3
#1
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
https://www.readbyqxmd.com/read/28698187/the-stoichiometry-%C3%AE-4-3-%C3%AE-2-2-of-the-nicotinic-acetylcholine-receptor-predominates-in-the-rat-motor-cortex
#2
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 normal CNS 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 that are referred to as high (HS) and low (LS) sensitivity nAChRs, respectively, based on a difference in the potency of acetylcholine to activate them. The physiological and pharmacological differences between these two receptor subtypes have been described in heterologous expression systems...
July 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28696214/epigenetic-regulation-by-agonist-specific-aryl-hydrocarbon-receptor-recruitment-of-metastatic-associated-protein-2-selectively-induces-stanniocalcin-2-expression
#3
Aditya D Joshi, Ekram Hossain, Cornelis J Elferink
The Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a plethora of target genes. Historically, the AhR has been studied as a regulator of xenobiotic metabolizing enzyme genes, notably cytochrome P4501A1 encoded by CYP1A1, in response to the exogenous prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AhR activity depends on binding to the xenobiotic response element (XRE) in partnership with the AhR nuclear translocator (Arnt). Recent studies identified stanniocalcin 2 (Stc2) as a novel AhR target gene responsive to the endogenous AhR agonist, cinnabarinic acid (CA)...
July 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28696213/ca-2-regulation-of-cav3-3-t-type-ca-2-channel-is-mediated-by-calmodulin
#4
Narae Lee, Sua Jeong, Kang-Chang Kim, Jin-Ah Kim, Jin-Yong Park, Ho-Won Kang, Edward Perez-Reyes, Jung-Ha Lee
Numerous investigations reported that increases of internal Ca(2+) (Ca(2+)i) pivotally regulate high voltage-activated (HVA) Ca(2+) channels via calmodulin (CaM). However, it is largely elusive that Ca(2+)i can regulate low voltage-activated T-type Ca(2+) channels. Using whole cell patch clamp, we compared the biophysical properties of Ca(2+) current through T-type Ca(2+) channel Cav3.1, Cav3.2, or Cav3.3 stably expressed in HEK293 cells between internal solutions containing 27 nM and l μM free Ca(2+) Both activation and inactivation kinetics of Cav3...
July 10, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28679508/a-system-independent-scale-%C3%AE-log-max-ec50-of-agonism-and-allosteric-modulation-for-assessment-of-selectivity-bias-and-receptor-mutation
#5
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
https://www.readbyqxmd.com/read/28674152/human-arylamine-n-acetyltransferase-1-is-inhibited-by-the-dithiocarbamate-pesticide-thiram
#6
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
https://www.readbyqxmd.com/read/28663280/megakaryocytic-smad4-regulates-platelet-function-through-syk-and-rock2-expression
#7
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
https://www.readbyqxmd.com/read/28663279/comparative-exploration-of-the-structure-activity-space-of-cloned-%C3%AE-like-octopamine-receptors-from-a-marine-and-a-terrestrial-arthropod
#8
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
https://www.readbyqxmd.com/read/28645932/a-functional-nav1-7-navab-chimera-with-a-reconstituted-high-affinity-protx-ii-binding-site
#9
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
https://www.readbyqxmd.com/read/28630263/determination-of-the-residues-in-the-extracellular-domain-of-the-nicotinic-%C3%AE-subunit-required-for-the-actions-of-physostigmine-on-neuronal-nicotinic-receptors
#10
Xiaochun Jin, Allison L Germann, Daniel J Shin, Gustav Akk, Joseph H Steinbach
Physostigmine can potentiate and inhibit neuronal nicotinic receptors, in addition to inhibiting the activity of acetylcholinesterase. We found that receptors containing 3 copies of the α2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing 3 copies of the α4 subunit that are potentiated. We exploited this observation to determine regions required for the actions of physostigmine. Chimeric constructs of the α2 and α4 subunits located two regions in the extracellular amino-terminal domain of the subunit: the E loop (a loop of the transmitter-binding domain) and a region closer to the amino-terminus that collectively could completely determine the different effects of physostigmine...
June 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28619748/pore-polarity-and-charge-determine-differential-block-of-kir1-1-and-kir7-1-potassium-channels-by-the-small-molecule-inhibitor-vu590
#11
Sujay Kharade, Jonathan Sheehan, Eric Figueroa, Jens Meiler, Jerod Denton
VU590 was the first publicly disclosed, sub-micromolar-affinity (IC50=0.2 µM), small-molecule inhibitor of the inward rectifier potassium (Kir) channel, Kir1.1, an emerging diuretic target for the treatment of hypertension. VU590 also inhibits Kir7.1, albeit with 40-fold lower potency (IC50~8 µM), and has been used as a Kir7.1 tool compound to uncover new roles of the channel in regulation of myometrial contractility and melanocortin signaling in the brain. Here, we employed molecular modeling, site-directed mutagenesis, and patch clamp electrophysiology to elucidate the molecular mechanisms underlying inhibition of Kir1...
June 15, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28615284/tcl1a-snps-and-estrogen-mediated-toll-like-receptor-myd88-dependent-nf-%C3%AE%C2%BAb-activation-snp-and-serm-dependent-modification-of-inflammation-and-immune-response
#12
Ming-Fen Ho, James N Ingle, Tim Bongartz, Krishna R Kalari, Paul E Goss, Lois E Shepherd, Taisei Mushiroda, Michiaki Kubo, Liewei Wang, Richard M Weinshilboum
In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy of breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol (E2), but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the "downstream" expression of a series of cytokines and chemokines and had a striking effect on NF-κB transcriptional activity...
June 14, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28588066/identification-of-aicp-as-a-glun2c-selective-nmda-receptor-superagonist-at-the-glun1-glycine-site
#13
Maja Jessen, Kristen Frederiksen, Feng Yi, Rasmus P Clausen, Kasper B Hansen, Hans Brauner-Osborne, Paul Kilburn, Anders Damholt
NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of D-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared to glycine and a partial agonist at GluN2B-containing receptors...
June 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28559424/c-x-c-motif-chemokine-receptor-3-splice-variants-differentially-activate-beta-arrestins-to-regulate-downstream-signaling-pathways
#14
Jeffrey S Smith, Priya Alagesan, Nimit K Desai, Thomas F Pack, Jiao-Hui Wu, Asuka Inoue, Neil J Freedman, Sudarshan Rajagopal
Biased agonism, the ability of different ligands for the same receptor to selectively activate some signaling pathways while blocking others, is now an established paradigm for GPCR signaling. One group of receptors in which endogenous bias is critical is the chemokine system, consisting of over 50 ligands and 20 receptors that bind one another with significant promiscuity. We have previously demonstrated that ligands for the same receptor can cause biased signaling responses. The goal of this study was to identify mechanisms that could underlie biased signaling between different receptor splice variants...
May 30, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28546421/statins-attenuate-activation-of-the-nlrp3-inflammasome-by-oxidized-ldl-or-tnf-%C3%AE-in-vascular-endothelial-cells-through-a-pxr-dependent-mechanism
#15
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
https://www.readbyqxmd.com/read/28546420/alterations-of-histone-modifications-contribute-to-pregnane-x-receptor-mediated-induction-of-cyp3a4-by-rifampicin
#16
Liang Yan, Yiting Wang, Jingyang Liu, Yali Nie, Xiaobo Zhong, Quancheng Kan, Lirong Zhang
Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of the clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3 acetylation and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3) in the CYP3A4 promoter...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28546419/direct-binding-of-the-corrector-vx-809-to-human-cftr-nbd1-evidence-of-an-allosteric-coupling-between-the-binding-site-and-the-nbd1-cl4-interface
#17
Rhea P Hudson, Jennifer E Dawson, P Andrew Chong, Zhengrong Yang, Linda Millen, Philip J Thomas, Christie G Brouillette, Julie D Forman-Kay
Understanding the mechanism of action of modulator compounds for the cystic fibrosis transmembrane conductance regulator (CFTR) is key for optimization of therapeutics as well as obtaining insights into the molecular mechanisms of CFTR function. We demonstrate direct binding of VX-809 to the first nucleotide-binding domain (NBD1) of human CFTR. Disruption of the interaction between C-terminal helices and the NBD1 core upon VX-809 binding is observed from chemical shift changes in the NMR spectra of residues in the helices and on the surface of β-strands S3, S9 and S10...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28495999/%C3%AE-arrestin-mediated-regulation-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel
#18
Matthew G Sangoi, Shawn M Lamothe, Jun Guo, Tonghua Yang, Wentao Li, Ellen G Avery, John T Fisher, Shetuan Zhang
The rapidly activating delayed rectifier K(+) channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome (LQTS). Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route...
May 11, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28536106/%C3%AE-2-subunit-containing-gabaa-receptor-subtypes-are-upregulated-and-contribute-to-alcohol-induced-functional-plasticity-in-the-rat-hippocampus
#19
A Kerstin Lindemeyer, Yi Shen, Ferin Yazdani, Xuesi M Shao, Igor Spigelman, Daryl L Davies, Richard W Olsen, Jing Liang
Alcohol (EtOH) intoxication causes changes in the rodent brain γ-aminobutyric acid receptor (GABAAR) subunit composition and function, playing a crucial role in EtOH withdrawal symptoms and dependence. Building evidence indicates that withdrawal from acute EtOH and chronic intermittent EtOH (CIE) results in decreased EtOH-enhanced GABAAR δ subunit-containing extrasynaptic and EtOH-insensitive α1βγ2 subtype synaptic GABAARs but increased synaptic α4βγ2 subtype, and increased EtOH sensitivity of GABAAR miniature postsynaptic currents (mIPSCs) correlated with EtOH dependence...
August 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28550097/correction-to-the-orphan-receptor-gpr17-is-unresponsive-to-uracil-nucleotides-and-cysteinyl-leukotrienes
#20
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July 2017: Molecular Pharmacology
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