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Molecular Pharmacology

Amy Hanna, Alexander Lam, Chris Thekkedam, Hermia Willemse, Angela Fay Dulhunty, Nicole Beard
The chemotherapeutic anthracycline metabolite doxorubicinol (doxOL) has been shown to interact with and disrupt the function of the cardiac ryanodine receptor Ca2+ release channel (RyR2) in the sarcoplasmic reticulum (SR) membrane and the SR Ca2+ binding protein calsequestrin2 (CSQ2). Normal increases in RyR2 activity in response to increasing diastolic SR [Ca2+] are influenced by CSQ2 and are disrupted in arrhythmic conditions. Therefore we explored the action of doxOL on RyR2's response to changes in luminal [Ca2+] seen during diastole...
September 15, 2017: Molecular Pharmacology
Alexey Pronin, Qiang Wang, Vladlen Z Slepak
Pilocarpine is a prototypical drug used to treat glaucoma and dry mouth and classified as either a full or partial muscarinic agonist. Here, we report several unexpected results pertaining to its interaction with muscarinic M3 receptor (M3R). We found that pilocarpine was 1,000 times less potent in stimulating mouse eye pupil constriction than muscarinic agonists oxotremorin-M (Oxo-M) or carbachol (CCh), even though all three ligands have similar Kd values for M3R. In contrast to CCh or Oxo-M, pilocarpine does not induce Ca2+ mobilization via endogenous M3R in HEK293T or mouse insulinoma MIN6 cells...
September 11, 2017: Molecular Pharmacology
Yi-Ting Chiu, Chongguang Chen, Daohai Yu, Stefan Schulz, Lee-Yuan Liu-Chen
We reported previously that the selective agonist U50,488H promoted phosphorylation of the mouse kappa opioid receptor (KOPR) at residues S356, T357, T363 and S369. Here, we found that agonist (U50,488H)-dependent KOPR phosphorylation at all the residues were mediated by Gi/oα proteins and multiple protein kinases [GRKs2, 3, 5 and 6 and protein kinase C (PKC)]. In addition, PKC activation by phorbol ester induced agonist-independent KOPR phosphorylation. Compared with U50,488H, PKC activation promoted much higher S356/T357 phosphorylation, much lower T363 phosphorylation and similar levels of S369 phosphorylation...
September 11, 2017: Molecular Pharmacology
Yunosuke Nakata, Toshinori Fuse, Kohei Yamato, Miho Asahi, Kunimitsu Nakahira, Fumiyo Ozoe, Yoshihisa Ozoe
Fluralaner (BravectoTM) is a recently marketed isoxazoline ectoparasiticide. This compound potently inhibits γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and less potently glutamate-gated chloride channels (GluCls) in insects. The mechanism underlying this selectivity is unknown. Therefore, we sought to identify the amino acid residue(s) causing the low potency of fluralaner toward GluCls. We examined the fluralaner sensitivity of mutant housefly (Musca domestica) GluCls in which amino acid residues in the transmembrane subunit interface (TSI) were replaced with the positionally equivalent amino acids of Musca GABACls...
September 8, 2017: Molecular Pharmacology
Emily J A Taylor, Evangelia Pantazaka, Kathryn L Shelley, Colin W Taylor
In human aortic smooth muscle cells (ASMC), prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca(2+) concentration ([Ca(2+)]i) evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca(2+) signals by PGE2 Exchange proteins activated by cAMP (EPACs) were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca(2+) signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3 The rate of Ca(2+) removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation...
September 6, 2017: Molecular Pharmacology
Zhan-Guo Gao, Kenneth A Jacobson
Traditionally, GPCR antagonists are classified as competitive or non-competitive and surmountable or insurmountable based on functional antagonism. P2Y1 receptor (P2Y1R) structures showed two antagonists binding to two spatially distinct sites: nucleotide MRS2500 (orthosteric, contacting the helical bundle) and urea BPTU (allosteric, on the external receptor surface). However, the nature of their P2Y1R antagonism has not been characterized. Here we characterized BPTU antagonism at various signaling pathways activated by structurally diverse agonists...
September 1, 2017: Molecular Pharmacology
Hendrik Ungefroren, David Witte, Koichiro Mihara, Bernhard H Rauch, Petra Henklein, Olaf Johren, Shirin Bonni, Utz Settmacher, Hendrik Lehnert, Morley D Hollenberg, Roland Kaufmann, Frank Gieseler
Transforming growth factor-β (TGF-β), serine proteinases such as trypsin, and proteinase-activated receptor 2 (PAR2) promote tumor development by stimulating invasion and metastasis. Previously, we found that in cancer cells derived from pancreatic ductal adenocarcinoma (PDAC) PAR2 protein is necessary for TGF-β1-dependent cell motility (Zeeh et al., 2016). Here, we show in the same cells that, conversely, the type I TGF-β; receptor ALK5 is dispensable for trypsin and PAR2 activating peptide (PAR2-AP)-induced migration...
August 25, 2017: Molecular Pharmacology
Hisashi Wakita, Tatsuya Yanagawa, Yoshikazu Kuboi, Toshio Imai
The chemokine fractalkine (CX3C chemokine ligand 1; CX3CL1) and its receptor, CX3CR1, are involved in the pathogenesis of several diseases, including inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, rheumatoid arthritis, hepatitis, myositis, multiple sclerosis, renal ischemia, and atherosclerosis. There are no orally available agents that modulate the fractalkine/CX3CR1 axis. E6130 is an orally available highly selective modulator of CX3CR1 that may be effective for treatment of inflammatory bowel disease...
August 25, 2017: Molecular Pharmacology
Amanda M Gleixner, Daniel F Hutchison, Sara Sannino, Tarun N Bhatia, Lillian C Leak, Patrick T Flaherty, Peter Wipf, Jeffrey L Brodsky, Rehana K Leak
N-Acetyl-L-cysteine (NAC) exhibits protective properties in brain injury models and has undergone a number of clinical trials. Most studies of NAC have focused on neurons. However, neuroprotection may be complemented by the protection of astrocytes because healthier astrocytes can better support the viability of neurons. Here we show that NAC can protect astrocytes against protein misfolding stress (proteotoxicity), the hallmark of neurodegenerative disorders. Although NAC is thought to be a glutathione precursor, NAC protected primary astrocytes from the toxicity of the proteasome inhibitor MG132 without eliciting any increase in glutathione...
August 22, 2017: Molecular Pharmacology
Maroua Jalouli, Sophie Mokas, Catherine A Turgeon, Laurent Lamalice, Darren E Richard
Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are an essential part for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC). AngII increases HIF-1 transcriptional activity by modulating specific signaling pathways. In VSMC, p42/p44 mitogen-activated protein kinase (MAPK) pathway activation is essential for HIF-1-mediated transcription during AngII treatment...
August 16, 2017: Molecular Pharmacology
Daniel J Shin, Allison L Germann, Joseph H Steinbach, Gustav Akk
Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has found that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear...
August 8, 2017: Molecular Pharmacology
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October 2017: Molecular Pharmacology
Dorit Möhrle, Katrin Reimann, Steffen Wolter, Markus Wolters, Ksenya Varakina, Evanthia Mergia, Nicole Eichert, Hyun-Soon Geisler, Peter Sandner, Peter Ruth, Andreas Friebe, Robert Feil, Ulrike Zimmermann, Doris Koesling, Marlies Knipper, Lukas Rüttiger
Nitric oxide (NO) activates the NO-sensitive soluble guanylate cyclase (NO-GC, sGC) and triggers intracellular signaling pathways involving cGMP. For survival of cochlear hair cells and preservation of hearing, NO-mediated cascades have both protective and detrimental potential. Here we examine the cochlear function of mice lacking one of the two NO-sensitive guanylate cyclase isoforms [NO-GC1 knockout (KO) or NO-GC2 KO]. The deletion of NO-GC1 or NO-GC2 did not influence electromechanical outer hair cell (OHC) properties, as measured by distortion product otoacoustic emissions, neither before nor after noise exposure, nor were click- or noise-burst-evoked auditory brainstem response thresholds different from controls...
October 2017: Molecular Pharmacology
Anastasios Chanalaris, Christine Doherty, Brian D Marsden, Gabriel Bambridge, Stephen P Wren, Hideaki Nagase, Linda Troeberg
Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1)...
October 2017: Molecular Pharmacology
Muhammad Imran Sohail, Diethart Schmid, Katrin Wlcek, Matthias Spork, Gergely Szakács, Michael Trauner, Thomas Stockner, Peter Chiba
The bile salt export pump (BSEP/ABCB11) transports bile salts from hepatocytes into bile canaliculi. Its malfunction is associated with severe liver disease. One reason for functional impairment of BSEP is systemic administration of drugs, which as a side effect inhibit the transporter. Therefore, drug candidates are routinely screened for potential interaction with this transporter. Hence, understanding the functional biology of BSEP is of key importance. In this study, we engineered the transporter to dissect interdomain communication paths...
October 2017: Molecular Pharmacology
Hoa T N Phan, Benita Sjögren, Richard R Neubig
Regulator of G protein signaling 2 (RGS2) plays a significant role in alleviating vascular contraction and promoting vascular relaxation due to its GTPase accelerating protein activity toward Gαq. Mice lacking RGS2 display a hypertensive phenotype, and several RGS2 missense mutations have been found predominantly in hypertensive human subjects. However, the mechanisms whereby these mutations could impact blood pressure is unknown. Here, we selected 16 rare, missense mutations in RGS2 identified in various human exome sequencing projects and evaluated their ability to inhibit intracellular calcium release mediated by angiotensin II receptor type 1 (AT1R)...
October 2017: Molecular Pharmacology
Emilia Kansanen, Suvi M Kuosmanen, Anna-Kaisa Ruotsalainen, Heidi Hynynen, Anna-Liisa Levonen
Nitro-fatty acids are reactive signaling mediators that are formed when unsaturated fatty acids react with nitric oxide or nitric oxide-derived species. Nitro-fatty acids can modify specific signaling pathways via post-translational modifications of Cys residues in key regulatory proteins. One of the signaling cascades activated by nitro-fatty acids is the Keap1-Nrf2 pathway. We have previously studied the effects of nitro-oleic acid (OA-NO2) on the human endothelial cell transcriptome. We observed that endothelin receptor B [ET-B (gene name EDNRB)], the receptor mediating the vasodilatory effects of endothelin-1 (ET-1) is induced by OA-NO2 Inasmuch as ET-1 is one of the key regulators of vascular tone, we chose to examine in more detail the effect of OA-NO2 on endothelin signaling in human endothelial cells...
October 2017: Molecular Pharmacology
Brandon M Brown, Heesung Shim, Miao Zhang, Vladimir Yarov-Yarovoy, Heike Wulff
Intermediate-conductance (KCa3.1) and small-conductance (KCa2) calcium-activated K(+) channels are gated by calcium binding to calmodulin (CaM) molecules associated with the calmodulin-binding domain (CaM-BD) of these channels. The existing KCa activators, such as naphtho[1,2-d]thiazol-2-ylamine (SKA-31), 6,7-dichloro-1H-indole-2,3-dione 3-oxime (NS309), and 1-ethylbenzimidazolin-2-one (EBIO), activate both channel types with similar potencies. In a previous chemistry effort, we optimized the benzothiazole pharmacophore of SKA-31 toward KCa3...
October 2017: Molecular Pharmacology
Andrea Martella, Huub Sijben, Arne C Rufer, Uwe Grether, Juergen Fingerle, Christoph Ullmer, Thomas Hartung, Adriaan P IJzerman, Mario van der Stelt, Laura H Heitman
The endocannabinoid system, and in particular the cannabinoid type 2 receptor (CB2R), raised the interest of many medicinal chemistry programs for its therapeutic relevance in several (patho)physiologic processes. However, the physico-chemical properties of tool compounds for CB2R (e.g., the radioligand [(3)H]CP55,940) are not optimal, despite the research efforts in developing effective drugs to target this system. At the same time, the importance of drug-target binding kinetics is growing since the kinetic binding profile of a ligand may provide important insights for the resulting in vivo efficacy...
October 2017: Molecular Pharmacology
Zhihui Zheng, Zanmei Zhao, Shuqiang Li, Xinhua Lu, Mengxi Jiang, Jie Lin, Yunqi An, Yang Xie, Meishu Xu, Wenbin Shen, Grace L Guo, Yixian Huang, Song Li, Xuexia Zhang, Wen Xie
Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose, and lipids. FXR agonists have shown promise for the treatment of NAFLD. In this study, we report altenusin (2076A), a natural nonsteroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3...
October 2017: Molecular Pharmacology
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