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Molecular Pharmacology

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https://read.qxmd.com/read/30770456/protocol-dependent-differences-in-ic50-values-measured-in-herg-assays-occur-in-a-predictable-way-and-can-be-used-to-quantify-state-preference-of-drug-binding
#1
William Lee, Monique J Windley, Matthew D Perry, Jamie I Vandenberg, Adam Hill
Current guidelines around preclinical screening for drug-induced arrhythmias require the measurement of the potency of block of Kv11.1 channels as a surrogate for risk. A shortcoming of this approach is that the measured IC50 of Kv11.1 block varies widely depending on the voltage protocol used in electrophysiological assays. In this study, we aimed to investigate the factors that that contribute to these differences and to identify whether it is possible to make predictions about protocol-dependent block that might facilitate comparison of potencies measured using different assays Our data demonstrate that state preferential binding, together with drug binding kinetics and trapping, is an important determinant of the protocol-dependence of Kv11...
February 15, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30765461/statins-perturb-g%C3%AE-%C3%AE-signaling-and-cell-behaviors-in-a-g%C3%AE-subtype-dependent-manner
#2
Mithila Tennakoon, Dinesh Kankanamge, Kanishka Senarath, Zehra Fasih, Ajith Karunarathne
Guanine nucleotide-binding proteins (G proteins) facilitate transduction of external signals to the cell interior, regulate a majority of eukaryotic signaling, and thus have become crucial disease drivers. G proteins largely function at the inner leaflet of the plasma membrane (PM) using covalently attached lipid anchors. Both small monomeric and heterotrimeric G proteins are primarily prenylated, either with a 15-carbon farnesyl or a 20-carbon geranylgeranyl polyunsaturated lipid. The mevalonate (HMG-CoA reductase) pathway synthesizes lipids for G protein prenylation...
February 14, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30745320/the-role-of-ackr3-in-breast-lung-and-brain-cancer
#3
Maria Neves, Amos Fumagalli, Jelle van den Bor, Philippe Marin, Martine J Smit, Federico Mayor
Recent reports regarding the significance of chemokine receptors in disease have put a spotlight on ACKR3. This atypical chemokine receptor is overexpressed in numerous cancer types and has been involved in the modulation of tumour cell proliferation and migration, tumour angiogenesis or resistance to drugs, thus contributing to cancer progression and metastasis occurrence. Here we focus on the clinical significance and potential mechanisms underlying the pathological role of ACKR3 in breast, lung and brain cancer and discuss its possible relevance as prognostic factor and potential therapeutic target in these contexts...
February 11, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30739093/a-comparison-of-the-ability-of-leu-8-and-pro-8-oxytocin-to-regulate-intracellular-ca-2-and-ca-2-activated-k-channels-at-human-and-marmoset-oxytocin-receptors
#4
Marsha L Pierce, Suneet Mehrotra, Aaryn C Mustoe, Jeffrey A French, Thomas F Murray
The neurohypophyseal hormone oxytocin (OT) regulates biological functions in both peripheral tissues and the central nervous system (CNS). In the CNS, OT influences social processes including peer relationships, maternal-infant bonding and affiliative social relationships. In mammals, the nonapeptide OT structure is highly conserved with leucine in the 8th position (Leu8 -OT). In marmosets ( Callithrix ) a nonsynonymous nucleotide substitution in the OXT gene codes for proline in the 8th residue position (Pro8 -OT)...
February 9, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30737253/how-does-p2x7-receptor-work-a-mechanism-based-approach-to-p2x7-receptor-action
#5
Mehmet Ugur, Ozlem Ugur
Ligand-gated ion channel P2X7 receptor attracts special attention due to its widespread presence as well as its unusual responses. Besides relatively well understood mechanisms such as intracellular Ca2+ increase and K+ depletion, P2X7 receptor activates other peculiar responses whose mechanisms are not fully understood. The best known among these is the permeabilization of the cell membrane to large molecules. This permeabilization has been explained by the activation of a non-selective permeation pathway by the P2X7 receptor, a phenomenon called "pore formatio"...
February 8, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30737252/ti0-8o2-nanosheets-inhibit-lung-cancer-stem-cells-by-inducing-production-of-superoxide-anion
#6
Nalinrat Petpiroon, Narumol Bhummaphan, Rapeepun Soonnarong, Wipa Chantarawong, Tosapol Maluangnont, Varisa Pongrakhananon, Pithi Chanvorachote
Recent research into the cancer stem cell (CSC) concept has driven progress in the understanding of cancer biology and has revealed promising CSC-specific targets with regard to drug discovery. As malignancies of lung cancer have been shown to be strongly associated with activities of CSCs, we examined the effects of Ti0.8O2 nanosheets on these cells. Here we show that the nanosheets target lung CSCs, but not normal primary dermal papilla (DP) stem cells. Whilst Ti0. 8O2 caused a dramatic apoptosis along with a decrease in CSC phenotypes, such nanosheets minimally affected those aspects in primary human DP cells...
February 8, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30723091/dynamic-opioid-receptor-regulation-in-the-periphery
#7
Nathaniel A Jeske
Opioids serve a vital role in the current analgesic array of treatment options. They are useful in acute instances involving severe pain associated with trauma, surgery, and in terminal diseases such as cancer. In the past three decades, multiple receptor isoforms and conformations have been reported throughout literature. Most of these studies conducted systemic analyses of opioid receptor function, often generalizing findings from receptor systems in central nervous tissue or exogenously-expressing immortalized cell lines as common mechanisms throughout physiology...
February 5, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30696720/monod-wyman-changeux-allosteric-shift-analysis-in-mutant-%C3%AE-1%C3%AE-3%C3%AE-2l-gabaa-receptors-indicates-selectivity-and-cross-talk-among-intersubunit-transmembrane-anesthetic-sites
#8
Andrea Szabo, Anahita Nourmahnad, Elizabeth Halpin, Stuart A Forman
BACKGROUND: Propofol, etomidate, and barbiturate anesthetics are allosteric co-agonists at pentameric α1β3γ2 GABAA receptors, modulating channel activation via four biochemically established inter-subunit transmembrane pockets. Etomidate selectively occupies the two β+/α- pockets, the barbiturate photolabel R-mTFD-MPAB occupies homologous α+/β- and γ+/β- pockets, and propofol occupies all four. Functional studies of mutations at M2-15' or M3-36' loci abutting these pockets provide conflicting results regarding their relative contributions to propofol modulation...
January 29, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30696719/derivatives-of-piperazines-as-potential-therapeutic-agents-for-alzheimer-s-disease
#9
Elena Popugaeva, Daria Cherniuk, Hua Zhang, Tatiana Postnikova, Karina Pac, Elena Fedorova, Vladimir Poroikov, Alexey Zaitsev, Ilya Bezprozvanny
Alzheimer's disease is the neurodegenerative disorder that is a major cause of dementia in the elderly. There is no cure against AD. We have recently discovered novel TRPC6-mediated intracellular signaling pathway that regulates stability of dendritic spines and plays a role in memory formation. We have previously shown that TRPC6 agonists exert beneficial effects in models of AD and may serve as lead compounds for development of AD therapeutic agents. In the current study, we used Integrity database to search for additional TRPC6 agonists...
January 29, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30696718/insights-into-the-regulatory-properties-of-human-adenylyl-cyclase-type-9
#10
Tanya A Baldwin, Yong Li, Cameron S Brand, Val J Watts, Carmen W Dessauer
Membrane bound adenylyl cyclase (AC) isoforms have distinct regulatory mechanisms that contribute to specificity of signaling and physiological roles. While insight into the physiological relevance of AC9 has progressed, the understanding of AC9 regulation is muddled with conflicting studies. Currently, modes of AC9 regulation include stimulation by Gαs, protein kinase C βII (PKCβII), or calcium-calmodulin kinase II (CaMKII) and inhibition by Gαi/o, novel PKC isoforms, or calcium-calcineurin. Conversely, the original cloning of human AC9 reported it insensitive to Gαi inhibition...
January 29, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30679204/trans-anethole-of-fennel-oil-is-a-selective-and-non-electrophilic-agonist-of-the-trpa1-ion-channel
#11
Tosifa Memon, Oleg Yarishkin, Christopher A Reilly, David Krizaj, Baldomero M Olivera, Russell W Teichert
Transient receptor potential (TRP) cation channels are molecular targets of various natural products. TRPA1 is specifically activated by natural products like allyl isothiocyanate (mustard oil), cinnamaldehyde (cinnamon), and allicin (garlic). In this study, we demonstrate that TRPA1 is also a target of trans-anethole in Fennel Oil (FO) and fennel seed extract. Similar to FO, trans-anethole selectively elicited calcium influx in TRPA1-expressing mouse sensory neurons of the dorsal root and trigeminal ganglia...
January 24, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30674565/mir-144-inhibits-tumor-growth-and-metastasis-in-osteosarcoma-via-dual-suppressing-rhoa-rock1-signaling-pathway
#12
Jin Long Liu, Jing Li, Jia Jia Xu, Fei Xiao, Peng Lei Cui, Zhi Guang Qiao, Xiao Ling Zhang
Background Several miRNAs have been found expressed differentially in osteosarcoma (OS), thus they may function in the onset and progression of osteosarcoma. Method The osteosarcoma cell proliferation ability was evaluated by CCK8 assay, cell cycle and colony formation assay in vitro and xenograft NOD mice model in vivo. The osteosarcoma cell mortality was analyzed by wound healing assay and transwell invasion assay in vitro and by zebrafish cancer metastasis model in vivo. The level of miR-144 were detected by real-time PCR and ISH...
January 23, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30670482/the-role-of-heat-shock-proteins-in-regulating-receptor-signal-transduction
#13
John Michael Streicher
Heat shock proteins (Hsp) are a class of stress-inducible proteins that mainly act as molecular protein chaperones. This chaperone activity is diverse, including assisting in nascent protein folding, and regulating client protein location and translocation within the cell. The main proteins within this family, particularly Hsp70 and Hsp90, also have a highly diverse and numerous set of protein clients, which when combined with the high expression levels of these proteins (2%-6% of total protein content), establishes these molecules as "central regulators" of cell protein physiology...
January 22, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30670481/chronic-menthol-does-not-change-stoichiometry-or-functional-plasma-membrane-levels-of-mouse-%C3%AE-3%C3%AE-4-containing-nicotinic-acetylcholine-receptors
#14
Selvan Bavan, Charlene H Kim, Brandon J Henderson, Henry A Lester
Heteromeric α3β4 nAChRs are pentameric ligand-gated cation channels that include at least two α3 and at least two β4 subunits. They have functions in peripheral tissue, peripheral and central nervous systems. We examined the effects of chronic treatment with menthol, a major flavor additive in tobacco cigarettes and in electronic nicotine delivery systems, on mouse α3β4 nAChRs transiently transfected into neuroblastoma 2a (Neuro-2a) cells. Chronic menthol treatment at 500 nM, near the estimated menthol concentration in the brain following cigarette smoking, altered neither the [ACh]-response relationship nor Zn2+ sensitivity of ACh-evoked currents, suggesting that menthol does not change α3β4 nAChR subunit stoichiometry...
January 22, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30665971/blockade-of-the-human-ether-a-go-go-related-gene-herg-potassium-channel-by-fentanyl
#15
Jared N Tschirhart, Wentao Li, Jun Guo, Shetuan Zhang
The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr ). Drug- or medical condition-mediated disruption of hERG function is the primary cause of acquired long QT syndrome (LQTS), which predisposes affected individuals to ventricular arrhythmias and sudden death. Fentanyl abuse poses a serious health concern, with abuse and death rates rising over recent years. As fentanyl has a propensity to cause sudden death, we investigated its effects on the hERG channel...
January 21, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30622215/belinostat-at-its-clinically-relevant-concentrations-inhibits-rifampicin-induced-cyp3a4-and-mdr1-gene-expression
#16
Kodye L Abbott, Chloe S Chaudhury, Aneesh Chandran, Saraswathi Vishveshwara, Zdenek Dvorak, Eva Jiskrova, Karolina Poulikova, Barbora Vyhlidalova, Sridhar Mani, Satyanarayana R Pondugula
Activation of human pregnane X receptor (hPXR) has been associated with induction of chemoresistance. It has been proposed that such chemoresistance via cytochromes P450/drug transporters can be reversed with use of antagonists that specifically abrogate agonist-mediated hPXR activation. Unfortunately, proposed antagonists lack specificity and appropriate pharmacological characteristics that allow these features to be active in the clinic. We propose that, ideally, a hPXR antagonist would be a cancer drug itself that is part of a "cancer drug cocktail&rdquo", and effective as a hPXR antagonist at therapeutic concentrations...
January 8, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30622214/inhibition-of-interleukin-10-transcription-through-the-smad2-3-signaling-pathway-by-ca-2-activated-k-channel-k-ca-3-1-activation-in-human-t-cell-lymphoma-hut-78-cells
#17
Miki Matsui, Junko Kajikuri, Hiroaki Kito, Kyoko Endo, Yuki Hasegawa, Shin-Ya Murate, Susumu Ohya
The hyperpolarization induced by intermediate-conductance Ca2+ -activated K+ channel (KCa 3.1) activation increases the driving force for Ca2+ influx, which generally promotes cell proliferation, migration, and cytokine production in immunocompetent cells. Interleukin-10 (IL-10) from tumor-infiltrating lymphocytes and macrophages, lymphoma, and carcinoma cells facilitates escape from tumor immune surveillance; however, the role of KCa 3.1 in IL-10 production remains unclear. The objective of the present study is to elucidate the involvement of KCa 3...
January 8, 2019: Molecular Pharmacology
https://read.qxmd.com/read/30593458/mexiletine-block-of-voltage-gated-sodium-channels-isoform-and-state-dependent-drug-pore-interactions
#18
Hiroki Nakagawa, Tatsuo Munakata, Akihiko Sunami
Mexiletine is a class Ib antiarrhythmic drug and is also used clinically to reduce or prevent myotonia. Mexiletine also has neuroprotective effects in the models of brain ischemia. We compared state-dependent affinities of mexiletine for Nav1.2, Nav1.4 and Nav1.5, and examined the effects of mutations of S6 residues in Nav1.5 affecting local anesthetic binding on mexiletine block. Three channel isoforms had similar affinities of mexiletine for the rested state, and Nav1.4 and Nav1.5 had similar affinities for the open and inactivated states, while Nav1...
December 28, 2018: Molecular Pharmacology
https://read.qxmd.com/read/30591538/molecular-basis-of-action-of-a-small-molecule-positive-allosteric-modulator-pam-agonist-at-the-type-1-cholecystokinin-holoreceptor
#19
Aditya J Desai, Ingrid Mechin, Karthigeyan Nagarajan, Celine Valant, Denise Wootten, Polo C H Lam, Andrew Orry, Ruben Abagyan, Anil Nair, Patrick M Sexton, Arthur Christopoulos, Laurence J Miller
Allosteric modulation of receptors provides mechanistic safety while effectively achieving biological endpoints otherwise difficult or impossible to obtain by other means. The theoretical case has been made for the development of a positive allosteric modulator (PAM) of the type 1 cholecystokinin receptor (CCK1R) having minimal intrinsic agonist activity to enhance meal-induced satiety for the treatment of obesity, while reducing the risk of side effects and/or toxicity. Unfortunately, such a drug does not currently exist...
December 27, 2018: Molecular Pharmacology
https://read.qxmd.com/read/30591537/structural-basis-of-p97-inhibition-by-the-site-selective-anti-cancer-compound-cb-5083
#20
Wai Kwan Tang, Taivan Odzorig, Whitney Jin, Di Xia
Inhibition of p97, a key player in the ubiquitin-proteasome degradation pathway, has been proposed as a treatment for cancer. This concept was nearly realized recently when a potent p97 inhibitor, CB-5083, was developed and demonstrated broad antitumor activity in various tumor models. CB-5083 functions as a competitive inhibitor that binds selectively to the ATP-binding site of the D2 domain, although both the D1 and D2 ATPase sites of p97 are highly similar. Despite its promising anti-cancer activity, CB-5083 failed its Phase I clinical trials due to an unexpected off-target effect, which necessitates further improvement of the inhibitor...
December 27, 2018: Molecular Pharmacology
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