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Molecular Pharmacology

Thorsten Keller, Valentin Gorboulev, Thomas Mueller, Volker Dotsch, Frank Bernhard, Hermann Koepsell
Organic cation transporters OCT1 ( SLC22A1 ) and OCT2 ( SLC22A2 ) are critically involved in absorption and excretion of diverse cationic drugs. Because drug-drug interactions at these transporters may induce adverse drug effects in patients, in vitro testing for interaction with the human transporters during drug development is mandatory. Recent data performed with rat OCT1 (rOCT1) suggest that currently performed in vitro tests assuming one polyspecific binding site are insufficient. Here we measured binding and transport of model substrate 1-methyl-4-phenylpyridinium+ (MPP+ ) by cell-free-expressed fusion proteins of rOCT1 and various rOCT1 mutants with green fluorescent protein that were reconstituted into nanodiscs or proteoliposomes...
November 8, 2018: Molecular Pharmacology
Juan Sironi, Evelyn Aranda, Lars Ulrik Nordstrom, Edward L Schwartz
Lysosomes degrade cellular proteins and organelles, and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably mTORC1. The striking differences in the lysosomes of cancer versus normal cells suggest that the lysosome would be a target for drug development. While the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, named EAD1, that is structurally related to CQ but is 14-fold more potent...
November 8, 2018: Molecular Pharmacology
Emily S Gibson, Kevin M Woolfrey, Huiming Li, Patrick G Hogan, Raphael A Nemenoff, Lynn E Heasley, Mark L Dell'Acqua
Calcineurin (CaN) phosphatase signaling is regulated by targeting CaN to substrates, inhibitors, and scaffold proteins containing docking motifs with the consensus sequence of PxIxIT. Here, we identify docking of CaN to the γ isoform of MKK7, a component of the c-Jun N-terminal kinase (JNK) pathway. Due to alternative splicing of a single exon within the N-terminal domain, MKK7γ encodes a unique PxIxIT motif (PIIVIT) that is not present in MKK7 α or β. We found that MKK7γ bound directly to CaN through this PIIVIT motif in vitro, immunoprecipitated with CaN from cell extracts, and exhibited fluorescence resonance energy transfer (FRET) with CaN in the cytoplasm but not the nucleus of living cells...
November 7, 2018: Molecular Pharmacology
Marco S Doucet, Jean-Luc Jougleux, Samuel J Poirier, Marc Cormier, Jacob L Leger, Marc E Surette, Nicolas Pichaud, Mohamed Touaibia, Luc H Boudreau
The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12-hydroxyeicosatetraenoic acid (12(S)-HETE) lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)-lipoxygenase (12-LO) pathway...
November 7, 2018: Molecular Pharmacology
Yuichiro Kanno, Shuai Zhao, Naoya Yamashita, Nao Saito, Aoi Ujiie, Rie Iijima, Nami Kikawa, Kiyomitsu Nemoto, Yoshio Inouye
The nuclear receptor constitutive active/androstane receptor (CAR) controls genes involved in xenochemical metabolism. Although numerous cofactors have been reported to be involved in CAR-mediated transactivation, there remain unknown and poorly defined proteins recruited by CAR that have yet to be characterized. In this study, a novel CAR-interacting protein, cell cycle and apoptosis regulator 1 (CCAR1), has been identified by performing co-immunoprecipitation analysis using human hepatocarcinoma HepG2 cells expressing FLAG-epitope tagged CAR (FLAG-CAR)...
November 5, 2018: Molecular Pharmacology
Erbo Dong, Valentina Locci, Eleonora Gatta, Dennis R Grayson, Alessandro Guidotti
Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally-induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic and monoaminergic neurons. In order to test the above hypothesis, we targeted our scientific efforts on identifying whether the molecular epigenetic signature of post-mortem brains of SZ, SZA, and BP disorder patients are also present in the brains of adult mice born from dams prenatally restraint-stressed during gestation...
November 5, 2018: Molecular Pharmacology
Yoo Jin Oh, Hye Young Kim, Mi Hwa Lee, Sung Hwan Suh, Yongmun Choi, Tae-Gyu Nam, Woo Young Kwon, Sang Yeop Lee, Young Hyun Yoo
Non-alcoholic fatty liver disease (NAFLD) is an increasingly studied condition that may progress to end-stage liver disease. Although NAFLD was first described in 1980, a complete understanding of the mechanism and causes of this disease is still lacking. A previous study suggested that STAMP2 may be a suitable target for treating NAFLD. In the current study, we, performing a focused drug screening, found that cilostazol could be a potential STAMP2 enhancer. Thus, we examined whether cilostazol alleviates NAFLD through STAMP2...
October 26, 2018: Molecular Pharmacology
Michael McMahon, Shaohong Ding, Lourdes P Acosta-Jimenez, Remi Terranova, Marie-Apolline Gerard, Antonio Vitobello, Jonathan Moggs, Colin J Henderson, Charles R Wolf
The constitutive androstane receptor (CAR) is a xenobiotic sensor expressed in hepatocytes that activates genes involved in drug metabolism, lipid homeostasis, and cell proliferation. Much progress has been made in understanding the mechanism of activation of human CAR by drugs and xenobiotics. However, many aspects of the activation pathway remain to be elucidated. In this report, we have used viral constructs to express human CAR, its splice variants, and mutant CAR forms in hepatocytes from Car-/- mice in vitro and in vivo...
October 25, 2018: Molecular Pharmacology
Nadine Schafer, Prashanth Reddy Rikkala, Maike Veyhl-Wichmann, Thorsten Keller, Christian Ferdinand Jurowich, Dietmar Geiger, Hermann Koepsell
A domain of protein RS1 ( RSC1A1 ) termed RS1-Reg downregulates plasma membrane abundance of Na+ -D-glucose cotransporter SGLT1 by blocking the exocytotic pathway at the trans -Golgi. This effect is blunted by intracellular glucose but prevails when serine in a QSP motif is replaced by glutamate (RS1-Reg(S20E)). RS1-Reg binds to ornithine decarboxylase (ODC) and inhibits ODC in a glucose-dependent manner. Because ODC inhibitor difluoromethylornithine (DFMO) acts like RS1-Reg(S20E) and DFMO and RS1-Reg(S20E) are not cumulative, we raised the hypothesis that RS1-Reg(S20E) downregulates the exocytotic pathway of SGLT1 at the trans -Golgi by inhibiting ODC...
October 24, 2018: Molecular Pharmacology
Xiaoxi Lu, Ting Chan, Zhengqi Cheng, Tahiatul Shams, Ling Zhu, Michael Murray, Fanfan Zhou
The Organic Anion Transporting Polypeptides (OATPs) are important membrane proteins that mediate the cellular uptake of drugs and endogenous substances. OATP1A2 is widely distributed in many human tissues that are targeted in drug therapy; defective OATP1A2 leads to altered drug disposition influencing therapeutic outcomes. 5' AMP-activated protein kinase (AMPK) signalling plays an important role in the pathogenesis of the metabolic syndrome characterized by an increased incidence of type II diabetes and non-alcoholic fatty liver disease...
October 22, 2018: Molecular Pharmacology
Wenlong Zhang, Xiuping Zhang, Shaogang Qu
In order to maintain efficient synaptic communication, glutamate transporters re-uptake glutamate from the synaptic cleft and prevent glutamate concentrations from reaching neurotoxic levels. Mammalian EAATs contain a stretch of over 50 amino acids in TM4b-4c loop that is absent in the bacterial protein. To investigate the spatial proximity and functional significance of residues in glutamate transporter, cysteine pairs were introduced at positions A243 of TM4b-4c loop and T396 or A414 of TM7, respectively...
October 22, 2018: Molecular Pharmacology
Wakako Fujita, Mini Yokote, Ivone Gomes, Achla Gupta, Hiroshi Ueda, Lakshmi A Devi
Signaling by classic analgesics such as morphine is governed primarily by the relative abundance of opioid receptors at the cell surface and this is regulated by receptor delivery to, and retrieval from, the plasma membrane. While retrieval mechanisms such as receptor endocytosis have been extensively investigated, fewer studies have explored mechanisms of receptor maturation and delivery to the plasma membrane. A previous study implicated receptor chaperone proteins (RTPs) in the latter process. Since not much is known about regulation of RTP expression, we initiated studies examining the effect of chronic morphine administration on the levels of RTPs in the brain...
October 22, 2018: Molecular Pharmacology
Marta Quadri, Sumanta Garai, Ganesh A Thakur, Clare Stokes, Alican Gulsevin, Nicole A Horenstein, Roger L Papke
B-973 is an efficacious type II positive allosteric modulator (PAM) of α7 nicotinic acetylcholine receptors that, like 4BP-TQS and its active isomer GAT107, is able to produce direct allosteric activation in addition to potentiation of orthosteric agonist activity, which identifies it as an ago-PAM. We compare the properties of B-973B, the active enantiomer of B-973, to those of GAT107 in regard to separation of allosteric potentiation and activation. Both ago-PAMs are able to strongly activate mutants of α7 that are insensitive to standard orthosteric agonists like acetylcholine...
October 22, 2018: Molecular Pharmacology
Daniel J Shin, Allison L Germann, Douglas F Covey, Joseph H Steinbach, Gustav Akk
Under both physiological and clinical conditions the GABAA receptors are exposed to multiple agonists, including the transmitter GABA, endogenous or exogenous neuroactive steroids, and various GABAergic anesthetic and sedative drugs. The functional output of the receptor reflects the interplay among all active agents. We have investigated the activation of the concatemeric α1β2γ2L GABAA receptor by combinations of agonists. Simulations of receptor activity using the co-agonist model demonstrate that the response amplitude in the presence of agonist combinations is highly dependent on whether the paired agonists interact with the same or distinct sites...
October 18, 2018: Molecular Pharmacology
Joseph H Steinbach, Gustav Akk
The Monod-Wyman-Changeux (MWC) cyclic model was described as a kinetic scheme to explain enzyme function and modulation more than 50 years ago and was proposed as a model for understanding activation of transmitter-gated channels soon afterwards. More recently the MWC model has been used to describe the activation of the GABAA receptor by the transmitter, GABA, and drugs that bind to separate sites on the receptor. It is most interesting that the MWC formalism can also describe the interactions among drugs which activate the receptor...
October 17, 2018: Molecular Pharmacology
Caitlin A D Jagla, Caitlin E Scott, Yaliang Tang, Changjiang Qiao, Gabriel E Mateo-Semidey, Guillermo A Yudowski, Dai Lu, Debra A Kendall
CB1 is a G protein coupled receptor (GPCR) abundant in the central nervous system. It binds several compounds in its orthosteric site, including the endocannabinoids, arachidonoyl ethanolamide (anandamide; AEA) and 2-arachidonoyl glycerol (2-AG), and the plant-derived Δ9- tetrahydrocannabinol (THC), one of the main psychoactive components of marijuana. It primarily couples to Gi/o proteins to inhibit adenylate cyclase activity and typically induces downstream signaling that is Gi -dependent. Since this receptor is implicated in several maladies, such as obesity, pain, and neurodegenerative disorders, there is interest in developing therapeutics that selectively target this receptor...
October 15, 2018: Molecular Pharmacology
Lucy Kate Ladefoged, Lachlan Munro, Anders J Pedersen, Thomas Balle, Benny Bang-Andersen, Sarah C R Lummis, Birgit Schiott, Anders S Kristensen
5-HT3 receptors are ligand-gated ion channels that mediate neurotransmission by serotonin in the central nervous system. Pharmacological inhibition of 5-HT3 receptor activity has therapeutic potential in several psychiatric diseases, including depression and anxiety. The recently approved multimodal antidepressant vortioxetine has potent inhibitory activity at 5-HT3 receptors. Vortioxetine has an inhibitory mechanism that differs from classical 5-HT3 receptor competitive antagonists despite being believed to bind in the same binding site...
September 26, 2018: Molecular Pharmacology
Anna Herman, Mostafa El Mansari, Nika Adham, Béla Kiss, Bence Farkas, Pierre Blier
Cariprazine, an orally active and potent dopamine D3 -preferring D3 /D2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptors and antagonism at 5-HT2A and 5-HT2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats...
December 2018: Molecular Pharmacology
Atsushi Matsumoto, Yukifumi Uesono
The cutoff phenomenon associated with the effectiveness of long-chain alcohols in the induction of anesthesia is also observed for various antimicrobial activities, although the mechanism has remained unknown for over eight decades. The minimum inhibitory concentrations at 25°C for budding yeast growth exponentially decreased with increasing chain length of n -alcohols (C2 -C12 ), whereas alcohols ≥C13 lost the inhibitory effect. Thus, growth inhibition by n- alcohols obeys the Meyer-Overton correlation up to C12 and exhibits a cutoff phenomenon...
December 2018: Molecular Pharmacology
Christian R Marks, Brian C Shonesy, Xiaohan Wang, Jason R Stephenson, Colleen M Niswender, Roger J Colbran
Ca2+ /calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu5 ) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu5 is present in CaMKII α complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu5a directly interacts with purified Thr286-autophosphorylated (activated) CaMKII α However, the binding of CaMKII α to this CTD fragment is reduced by the addition of excess Ca2+ /calmodulin or by additional CaMKII α autophosphorylation at non-Thr286 sites...
December 2018: Molecular Pharmacology
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