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Molecular Pharmacology

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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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/28536106/alpha-2-subunit-containing-gabaa-receptor-subtypes-are-up-regulated-and-contribute-to-alcohol-induced-functional-plasticity-in-rat-hippocampus
#9
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 rodent brain GABAA receptor (GABAAR) subunit composition and function, playing a crucial role in EtOH withdrawal symptoms and dependence. Building evidence indicates 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...
May 23, 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
#10
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/28432201/mg53-biological-function-and-potential-as-a-therapeutic-target
#11
Yan Zhang, Hong-Kun Wu, Fengxiang Lv, Rui-Ping Xiao
MG53 (also known as TRIM72) is a cardiac and skeletal muscle-specific TRIM-family protein that exhibits multiple biological functions. First, MG53 participates in plasma membrane repair of the heart, skeletal muscle and other tissues. Second, MG53 is essentially involved in the cardioprotection of cardiac ischemic, pre-conditioning and post-conditioning, by activating the PI3K-Akt-GSK3β and ERK1/2 survival signaling pathways. Moreover, systemic delivery of recombinant MG53 protein ameliorates the impact of a range of injury insults on heart, skeletal muscle, lung, kidney, skin and brain...
April 21, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28424220/gababr-induced-egfr-transactivation-promotes-migration-of-human-prostate-cancer-cells
#12
Shuai Xia, Cong He, Yini Zhu, Suyun Wang, Huiping Li, Zhongling Zhang, Xinnong Jiang, Jianfeng Liu
G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) act in concert to regulate cell growth, proliferation, survival, and migration. Metabotropic GABAB receptor (GABABR) is the GPCR for the main inhibitory neurotransmitter GABA in the central nervous system. Increased expression of GABABR has been detected in human cancer tissues and cancer cell lines, but the role of GABABR in these cells is controversial and the underlying mechanism remains poorly understood. Here, we investigated whether GABABR hijacks RTK signaling to modulate the fates of human prostate cancer cells...
April 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28420679/tumor-microenvironment-targeting-and-responsive-peptide-based-nanoformulations-for-improved-tumor-therapy
#13
Hao Qin, Yanping Ding, Ayeesha Mujeeb, Ying Zhao, Guangjun Nie
Tumor microenvironment participates in all stages of tumor progression and has emerged as a promising therapeutic target for cancer therapy. Rapid progress in the field of molecular self-assembly using various biological molecules has resulted in the fabrication of nanoformulations, specifically targeting and regulating the microenvironment components to inhibit tumor malignancies. This inhibition process is based on the differentiating biophysicochemical cues guiding tumor and normal tissue microenvironments...
April 18, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28404616/progress-of-pharmacological-sciences-in-china
#14
Jian-Cheng Wang, Yungui Zhu, Lei Wu, Erdan Dong
Pharmacology is the science that investigates the interactions between organisms and drugs and their mechanisms. Pharmacology plays a translational role in modern medicine, bridging basic research to the clinic. With its booming economy, China has invested an enormous amount of financial and human resources on pharmacological research in the recent decade. As a result, major breakthroughs have been achieved in both basic and clinical research in this area with the discoveries of many potential drug targets and biomarkers, making a sizable contribution to the overall advancement of pharmacological sciences...
April 12, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28377424/the-ca2-permeable-cation-trpv3-channel-an-emerging-pivotal-target-for-itch-and-skin-diseases
#15
Gongxin Wang, Kewei Wang
Temperature-sensitive transient receptor potential (thermo-TRP) channels such as TRPA1 and TRPV1 have been indicated as downstream ion channel targets in transduction of itch. As a member of thermos-TRPs, Ca2+-permeable nonselective cation TRPV3 channels are expressed abundantly in the skin keratinocytes. Recent identification of gain-of-function mutations of human TRPV3 from patients with Olmsted Syndrome characterized by severe itching and palmoplantar and periorificial keratoderma unveils its crucial role in chronic itch and skin diseases...
April 4, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28356334/clinical-applications-of-circulating-tumor-cells-in-pharmacotherapy-challenges-and-perspectives
#16
Tong Wu, Bin Cheng, Liwu Fu
Circulating tumor cells (CTCs) have been identified as one of the ultrasensitive liquid biopsy for real-time monitoring cancer patients. The CTCs detection in peripheral blood from cancer patients has brought the hope, but still facing serious challenge on its specificity and sensitivity. Here, we review the significant roles of CTCs in metastasis, and the strength and weakness of currently available methods for CTCs detection and characterization. Moreover, we mainly discuss the clinical application of CTCs such as markers for patients' prognosis prediction, and we specifically focus on the application of CTCs as indicators in cancer pharmacotherapy...
March 29, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28550097/correction-to-the-orphan-receptor-gpr17-is-unresponsive-to-uracil-nucleotides-and-cysteinyl-leukotrienes
#17
(no author information available yet)
No abstract text is available yet for this article.
July 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28468946/novel-mode-of-antagonist-binding-in-nmda-receptors-revealed-by-the-crystal-structure-of-the-glun1-glun2a-ligand-binding-domain-complexed-to-nvp-aam077
#18
Annabel Romero-Hernandez, Hiro Furukawa
Competitive antagonists against N-methyl-D-aspartate (NMDA) receptors have played critical roles throughout the history of neuropharmacology and basic neuroscience. There are currently numerous NMDA receptor antagonists containing a variety of chemical groups. Among those compounds, a GluN2-specific antagonist, (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid (NVP-AAM077), contains a unique combination of a dioxoquinoxalinyl ring, a bromophenyl group, and a phosphono group...
July 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28461586/dexamethasone-downregulates-endothelin-receptors-and-reduces-endothelin-induced-production-of-matrix-metalloproteinases-in-cultured-rat-astrocytes
#19
Yutaka Koyama, Ayano Ukita, Kana Abe, Kuniaki Iwamae, Shogo Tokuyama, Keisuke Tanaka, Yuki Kotake
In brain disorders, astrocytes change phenotype to reactive astrocytes and are involved in the induction of neuroinflammation and brain edema. The administration of glucocorticoids (GCs), such as dexamethasone (Dex), reduces astrocytic activation, but the mechanisms underlying this inhibitory action are not well understood. Endothelins (ETs) promote astrocytic activation. Therefore, the effects of Dex on ET receptor expressions were examined in cultured rat astrocytes. Treatment with 300 nM Dex for 6-48 hours reduced the mRNA expression of astrocytic ETA and ETB receptors to 30-40% of nontreated cells...
July 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28461585/up-regulated-ectonucleotidases-in-fas-associated-death-domain-protein-and-receptor-interacting-protein-kinase-1-deficient-jurkat-leukemia-cells-counteract-extracellular-atp-amp-accumulation-via-pannexin-1-channels-during-chemotherapeutic-drug-induced-apoptosis
#20
Andrea M Boyd-Tressler, Graham S Lane, George R Dubyak
Pannexin-1 (Panx1) channels mediate the efflux of ATP and AMP from cancer cells in response to induction of extrinsic apoptosis by death receptors or intrinsic apoptosis by chemotherapeutic agents. We previously described the accumulation of extracellular ATP /AMP during chemotherapy-induced apoptosis in Jurkat human leukemia cells. In this study, we compared how different signaling pathways determine extracellular nucleotide pools in control Jurkat cells versus Jurkat lines that lack the Fas-associated death domain (FADD) or receptor-interacting protein kinase 1 (RIP1) cell death regulatory proteins...
July 2017: Molecular Pharmacology
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