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Molecular Pharmacology

Jing Li, Ji Jing, Yang Bai, Zhen Li, Roumei Xing, Binhe Tan, Xueyun Ma, Wenwei Qiu, Changsheng Du, Bing Du, Fan Yang, Jie Tang, Stefan Siwko, Mingyao Liu, Huaqing Chen, Jian Luo
CD4+ T helper cells, especially Th17 cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on pro-inflammatory cytokine IL-17 and IFN-γ production. In this study, we screened BA derivatives and found a BA derivative, SH479, which had a greater inhibitory effect on Th17 differentiation...
February 17, 2017: Molecular Pharmacology
Hai-Yun Wu, Xiao-Fang Mao, Hui Fan, Yong-Xiang Wang
Upon recent discovery, it has been established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) exhibits neuroprotection and antinociception through microglial β-endorphin expression. This study aims to explore its underlying signaling mechanisms. GLP-1Rs and β-endorphin were co-expressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the β-endorphin precursor gene POMC and peptide, with EC50 values of 4...
February 15, 2017: Molecular Pharmacology
Feifei Xu, Suzhen Sun, Xiaojun Wang, Eran Ni, Lingling Zhao, Weizhong Zhu
: Elevated interleukin 6(IL-6) levels in congestive heart failure are associated with myocardial damage during acute exacerbation and with chronic inflammation. Arginine vasopressin (AVP), a hormone released in response to cardiac stress, could be a factor of inflammation and fibrosis in the pathogenesis of heart failure. Recently, we have shown that AVP promotes the proliferation of neonatal rat cardiac fibroblasts (NRCFs) through a V1Avasopressin receptor-mediated G protein-coupled receptor kinase2 (GRK2) signaling...
February 13, 2017: Molecular Pharmacology
Sung Hye Kim, Oliver Pohl, Andre Chollet, Jean-Pierre Gotteland, Adam D J Fairhurst, Phillip R Bennett, Vasso Terzidou
One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labour. Apart from contractions, our recent study have shown that OT can also activate pro-inflammatory pathways in both human myometrial and amnion cells which suggests the pro-inflammatory role of OT should be taken into account when developing tocolytics targeting the OT/OT receptor (OT/OTR) system. The OTR antagonist, Atosiban, is currently used therapeutically for the treatment of PTL. We have previously shown that Atosiban fails to inhibit the pro-inflammatory effects of OT in human amnion, and Atosiban alone activates NF-κB and MAPKs thus upregulating downstream pro-labour genes...
February 10, 2017: Molecular Pharmacology
Shalley N Kudalkar, Jagadish Beloor, Albert H Chan, Won-Gil Lee, William L Jorgensen, Priti Kumar, Karen S Anderson
The clinical benefits of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers...
February 6, 2017: Molecular Pharmacology
Anna De Min, Carlo Matera, Andreas Bock, Janine Holze, Jessica Kloeckner, Mathias Muth, Christian Traenkle, Marco De Amici, Terry Kenakin, Ulrike Holzgrabe, Clelia Dallanoce, Evi Kostenis, Klaus Mohr, Ramona Schrage
Protean agonists are of great pharmacological interest as their behavior may change in magnitude and direction depending on the constitutive activity of a receptor. Yet, this intriguing phenomenon has been poorly described and understood, due to the lack of stable experimental systems and design strategies. Here, we overcome both limitations: First, we demonstrate that modulation of the ionic strength in a defined experimental set-up allows for analysis of GPCR activation in the absence and presence of a specific amount of spontaneous receptor activity using the muscarinic M2 acetylcholine receptor as a model...
February 6, 2017: Molecular Pharmacology
Zara Y Weinberg, Amanda S Zajac, Tiffany Phan, Daniel J Shiwarski, Manojkumar A Puthenveedu
Functional selectivity at the μ opioid receptor (μR), a prototypical GPCR that is a physiologically relevant target for endogenous opioid neurotransmitters and analgesics, has been a major focus for drug discovery in the recent past. The cellular mechanisms that mediate functional selectivity, however, are still being fully elucidated. The present work tested the hypothesis that lifetimes of agonist-induced receptor-arrestin clusters at the cell surface controls the magnitude of arrestin signaling, and therefore functional selectivity, on μR...
February 2, 2017: Molecular Pharmacology
Yadav Wagley, Ping-Yee Law, Li-Na Wei, Horace H Loh
Since the discovery of mu opioid receptor (MOR) gene two decades ago, various regulatory factors have been shown to interact with the MOR promoter and modulate transcript levels. However, the majority of early transcriptional studies on MOR gene have not addressed how intracellular signaling pathways mediate extracellular modulators. In this study, we demonstrate that MOR epigenetic regulation requires multiple co-ordinated signals converged at the MOR promoter, involving mitogen-activated protein kinase (MAPK) activation and mitogen-and stress-activated protein kinase (MSK1) - similar ranges of intracellular signaling pathways that are activated by opioid agonists...
February 2, 2017: Molecular Pharmacology
Rui Zhang, Isaac N Pessah
Bisphenol A (BPA) and its brominated derivative tetrabromobisphenol A (TBBPA) are high production volume chemicals utilized in the manufacture of various consumer products. Although regarded as endocrine disruptors, these chemicals are suspected to exert non-genomic actions on muscle function that are not well understood. Using skeletal muscle microsomes, we examined the effects of BPA and TBBPA on ryanodine receptor type 1 (RyR1), dihydropyridine receptor (DHPR), and sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA)...
January 31, 2017: Molecular Pharmacology
Wenjuan Chen, Anel Tankovic, Pieter B Burger, Hirofumi Kusumoto, Stephen F Traynelis, Hongjie Yuan
The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ionotropic glutamate receptor, plays important roles in normal brain development and a wide range of neurological disorders, including epilepsy. Here, we evaluate for the first time the functional properties of a de novo GRIN2A missense mutation (p.M817V) in the pre-M4 linker in a child with profound global developmental delay and refractory epilepsy. Electrophysiological recordings revealed that the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc), prolonged synaptic-like response time course, increased single channel mean open time, and increased channel open probability...
January 26, 2017: Molecular Pharmacology
Hai M Nguyen, Vikrant Singh, Brandon Pressly, David Paul Jenkins, Heike Wulff, Vladimir Yarov-Yarovoy
The calcium-activated potassium channel KCa3.1 constitutes an attractive pharmacological target for immunosuppression, fibroproliferative disorders, atherosclerosis and stroke. However, there currently is no available crystal structure of this medically relevant channel that could be used for structure-assisted drug design. Using the Rosetta molecular modeling suite we generated a molecular model of the KCa3.1 pore and tested the model by first confirming previously mapped binding sites and visualizing the mechanism of TRAM-34, senicapoc and NS6180 inhibition at the atomistic level...
January 26, 2017: Molecular Pharmacology
Rithwik Ramachandran, Koichiro Mihara, Pierre Thibeault, Christina M Vanderboor, Bjoern Petri, Mahmoud Saifeddine, Michel Bouvier, Morley D Hollenberg
Thrombin initiates human platelet aggregation by coordinately activating proteinase activated receptors (PARs)-1 and -4. However, targeting PAR1 with an orthostatic tethered ligand binding site antagonist results in bleeding, possibly due to the important role of PAR1 activation on cells other than platelets. Because of its more restricted tissue expression profile, we have therefore turned to PAR4 as an antiplatelet target. We have identified an intracellular PAR4 C-terminal motif that regulates calcium signaling and β-arrestin interactions...
January 26, 2017: Molecular Pharmacology
Jia-Rong Huang, Guang-Mou Tan, Yong Li, Zhi Shi
Cdk5 and Abl enzyme substrate (Cables) 1 is adaptor protein to link cyclin-dependent kinase (Cdks) with nonreceptor tyrosine kinases and regulate the activity of Cdks by enhancing their Y15 phosphorylation. The emerging evidences also show Cables1 can interact with p53 family proteins, 14-3-3, β-catenin and so on, suggesting Cables1 may be a signaling hub to regulate cell growth. Abnormal expression of Cables1 has been observed in multiple types of cancers and other disease. In this review, we summarize the characteristics of Cables1, and highlight the molecular mechanisms through which Cables1 regulates the development of cancer and other disease...
January 24, 2017: Molecular Pharmacology
Sooyeon Jo, Bruce P Bean
Lacosamide is an antiseizure agent targeting voltage-dependent sodium channels. Previous experiments have suggested that lacosamide is unusual in binding selectively to the slow-inactivated state of sodium channels, in contrast to drugs like carbamazepine and phenytoin that bind tightly to fast-inactivated states. We examined the state-dependent effects of lacosamide, using heterologously-expressed human Nav1.7 sodium channels. Lacosamide induced a reversible shift in the voltage-dependence of fast inactivation studied with 100 ms prepulses, suggesting binding to fast-inactivated states...
January 24, 2017: Molecular Pharmacology
Emily V Mesev, David S Miller, Ronald E Cannon
P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our lab has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries...
January 24, 2017: Molecular Pharmacology
Xiu-Lei Mo, Qi Qi, Andrei A Ivanov, Qiankun Niu, Yin Luo, Jonathan Havel, Russell Goetze, Sydney Bell, Carlos S Moreno, Lee A D Cooper, Margaret A Johns, Fadlo R Khuri, Yuhong Du, Haian Fu
The c-Myc (MYC) transcription factor is a major cancer driver and a well-validated therapeutic target. However, directly targeting MYC has been challenging. Thus, identifying proteins that interact with and regulate MYC may provide alternative strategies to inhibit its oncogenic activity. Here we report the development of a NanoLuc®-based protein-fragment complementation assay (NanoPCA) and mapping of the MYC protein interaction hub in live mammalian cells. The NanoPCA system was configured to enable detection of protein-protein interactions (PPI) at the endogenous level, as shown with PRAS40 dimerization, and detection of weak interactions, such as PINCH1-NCK2...
January 13, 2017: Molecular Pharmacology
Bin Huang, Suk-Hwan Baek
Ubiquitination is a versatile post-translational modification involved in NF-κB activation of TLR signaling. Here, we demonstrated that Trim13, an E3 ubiquitin ligase, is up-regulated in macrophages upon stimulation with TLR2 ligand. Knock-down of Trim13 attenuated TLR2-mediated production of cytokines/chemokines and formation of foam cells, as well as activation of NF-κB. Trim13 interacts with TRAF6 and potentiates NF-κB activity via ubiquitination of TRAF6. Overexpression of inactive mutant (C10/13A) or RING deletion mutant of Trim13 did not potentiate ubiquitination of TRAF6 or activation of NF-κB...
January 13, 2017: Molecular Pharmacology
Ni Li, Xiao Wang, Yanni Xu, Yuan Lin, Ningyu Zhu, Peng Liu, Duo Lu, Shuyi Si
Activation of Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes beneficial to anti-atherosclerosis. Nevertheless, existing agonists which target LXR, for example TO901317, are related to unwanted side-effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRα/β agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines...
January 13, 2017: Molecular Pharmacology
Daniel F Legler, Christoph Matti, Julia M Laufer, Barbara D Jakobs, Vladimir Purvanov, Edith Uetz-von Allmen, Marcus Thelen
Chemokine receptors are seven transmembrane-domain receptors belonging to class A of G protein-coupled receptors (GPCRs). The receptors together with their chemokine ligands constitute the chemokine system, which is essential for directing cell migration and plays a crucial role in a variety of physiological and pathological processes. Given the importance of orchestrating cell migration, it is vital that chemokine receptor signaling is tightly regulated to ensure appropriate responses. Recent studies highlight a key role for cholesterol in modulating chemokine receptor activities...
January 12, 2017: Molecular Pharmacology
Marco A Alfonzo-Mendez, David A Hernandez-Espinosa, Gabriel Carmona-Rosas, M Teresa Romero-Avila, Guadalupe Reyes-Cruz, J Adolfo Garcia-Sainz
Upon agonist stimulation, α1B-adrenergic receptors (α1B-ARs) couple to Gq, calcium signaling and protein kinase C activation; subsequently, the receptors are phosphorylated, desensitized and internalized. Internalization seems to involve scaffolding proteins, such as α-arrestin and clathrin. However, the fine mechanisms that participate remain unsolved. The roles of protein kinase C and the small GTPase, Rab9, in α1B-AR vesicular traffic were investigated by studying α1B-adrenergic receptor-Rab protein interactions, using Forster resonance energy transfer (FRET), confocal microscopy, and intracellular calcium quantitation...
January 12, 2017: Molecular Pharmacology
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