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Molecular Pharmacology

Adrian P Campbell, Laurence P G Wakelin, William A Denny, Angela M Finch
The α1 adrenergic receptors are targets for a number of cardiovascular and CNS conditions, however current drugs for these receptors lack specificity to be of optimal clinical value. Allosteric modulators offer an alternative mechanism of action to traditional α1 adrenergic ligands, yet there is little information describing this drug class at the α1 adrenergic receptors. We have identified a series of 9-aminoacridine compounds that demonstrate allosteric modulation of the α1A and α1B adrenergic receptors...
November 30, 2016: Molecular Pharmacology
Laura Nogues, Clara Reglero, Veronica Rivas, Maria Neves, Petronila Penela, Federico Mayor
Malignant features such as sustained proliferation, refractoriness to growth suppressors, resistance to cell death or aberrant motility and metastasis can be triggered by a variety of mutations and signaling adaptations. Signaling nodes can act as cancer-associated factors by cooperating with oncogene-governed pathways or participating in compensatory transduction networks to strengthen tumor properties. G-protein-coupled receptor kinase 2 (GRK2) is arising as one of such nodes. Via its complex network of connections with other cellular proteins, GRK2 contributes to the modulation of basic cellular functions such as cell proliferation, survival or motility, and is involved in metabolic homeostasis, inflammation or angiogenic processes...
November 28, 2016: Molecular Pharmacology
Lawrence C Blume, Theresa Patten, Khalil Eldeeb, Sandra Leone-Kabler, Alexander A Ilyasov, Bradley M Keegan, Jeremy E O'Neal, Caroline E Bass, Roy R Hantgan, W Todd Lowther, Dana E Selley, Allyn C Howlett
Cannabinoid Receptor Interacting Protein1a (CRIP1a) is a CB1 receptor (CB1R) distal C-terminus-associated protein that alters CB1R interactions with G-proteins (Blume et al.,2015; Smith et al.,2015). We tested the hypothesis that CRIP1a is capable of also altering CB1R interactions with β-arrestin proteins that interact with the CB1R at the C-terminal. Co-immunoprecipitation studies indicated that CB1R associates in complexes with either CRIP1a or β-arrestin, but CRIP1a and β-arrestin fail to co-immunoprecipitate with each other...
November 28, 2016: Molecular Pharmacology
Xiaochun Jin, Megan M McCollum, Allison L Germann, Gustav Akk, Joseph H Steinbach
Physostigmine is a well-known inhibitor of acetylcholinesterase, which can also activate, potentiate and inhibit acetylcholine receptors, including neuronal nicotinic receptors comprising α4 and β2 subunits. We have found that the two stoichiometric forms of this receptor differ in the effects of physostigmine. The form containing 3 copies of α4 and 2 of β2 was potentiated at low concentrations of ACh and physostigmine, while the form containing 2 copies of α4 and 3 of β2 was inhibited. Chimeric constructs of subunits indicated that the presence of inhibition or potentiation depended on the source of the extracellular ligand-binding domain of the subunit...
November 28, 2016: Molecular Pharmacology
Mahaveer Singh, Hemant Jadhav, Tanya B
Dynamin is a GTPase, which plays a vital role in clathrin dependent endocytosis and other vesicular trafficking processes. Dynamin acts as scissor with debatable mechanism for newly formed vesicles originating from plasma membrane. Dynamin related proteins are important components in scission of various organelles such as clathrin coated vesicles, phagosomes and mitochondria, etc. helping in organelle division, viral resistance and mitochondrial fusion/division. Dysfunction and mutations in dynamin have been implicated in various disorders, where endocytic trafficking is involved, such as Alzheimer's, Parkinson's, Huntington's, Charcot-Marie Tooth disease, Heart failure, Schizophrenia, Epilepsy, Cancer, Optic atrophy, Down syndrome, Osteoporosis etc...
November 22, 2016: Molecular Pharmacology
Nikoleta G Tsvetanova, Michelle Trester-Zedlitz, Billy W Newton, Daniel P Riordan, Aparna B Sundaram, Jeffrey R Johnson, Nevan J Krogan, Mark von Zastrow
The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications but, if excessively propagated downstream, would introduce biological 'noise' compromising cognate ligand detection. We asked if cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse β-adrenoceptor agonists, isoproterenol and salmeterol...
November 22, 2016: Molecular Pharmacology
Darren M Riddy, Anna Cook, Natalie A Diepenhorst, Sanja Bosnyak, Ryan Brady, Clotilde Mannoury-la-Cour, Elisabeth Mocaer, Roger J Summers, William Charman, Patrick M Sexton, Arthur Christopoulos, Christopher J Langmead
The human histamine H3 receptor (hH3R) is subject to extensive gene splicing that gives rise to a large number of functional and non-functional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signalling, this has not been studied for the H3R; further, it has unknown whether splice variants of the same receptor engender the same or differential biased signalling. Herein we have profiled the pharmacology of histamine receptor agonists at the two most abundant hH3R splice variants (hH3R445 and hH3R365) across seven signalling endpoints...
November 18, 2016: Molecular Pharmacology
Yasunori Uchida, Florentine U Rutaganira, Damien Jullie, Kevan M Shokat, Mark von Zastrow
G protein-coupled receptors (GPCRs), the largest family of signaling receptors, are critically regulated by endosomal trafficking, suggesting that endosomes might provide new strategies for manipulating GPCR signaling. Here we test this hypothesis by focusing on class III phosphatidylinositol (PI) 3-kinase or Vps34, an essential regulator of endosomal trafficking. We verify that Vps34 is required for recycling of the β2-adrenoceptor (β2AR), a prototypical GPCR, and then investigate the effects of Vps34 inhibition on the canonical cAMP response elicited by β2AR activation...
November 7, 2016: Molecular Pharmacology
Seiji Sato, Xi-Ping Huang, Wes Kroeze, Bryan L Roth
In this study, we identified two previously described kinase inhibitors-- LY2784544 and GSK2636771-- as novel GPR39 agonists by unbiased small-molecule-based screening using a βarrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared it with a previously described "GPR39-selective" agonist GPR39-C3 at both canonical and non-canonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by zinc...
October 17, 2016: Molecular Pharmacology
Marie-Laure Rives, Morena Shaw, Bin Zhu, Simon A Hinke, Alan Wickenden
In the liver, citrate is a key metabolic intermediate involved in the regulation of glycolysis and lipid synthesis and reduced expression of the hepatic citrate SLC13A5 transporter has been shown to improve metabolic outcomes in various animal models. Although inhibition of hepatic extracellular citrate uptake through SLC13A5 has been suggested as a potential therapeutic approach for Type-2 diabetes and/or fatty liver disease, so far, only a few SLC13A5 inhibitors have been identified. Moreover, their mechanism of action still remains unclear, potentially limiting their utility for in vivo proof-of-concept studies...
October 17, 2016: Molecular Pharmacology
Hannah E Majeski, Jing Yang
Past decades of cancer research have mainly focused on the role of various extracellular and intracellular biochemical signals on cancer progression and metastasis. Recent studies suggest an important role of mechanical forces in regulating cellular behaviors. This review first provides an overview of the mechanobiology research field. Then we specially focus on mechanotransduction pathways in cancer progression and describe in detail the key signaling components of such mechanotransduction pathways and ECM components that are altered in cancer...
October 14, 2016: Molecular Pharmacology
Anh Tn Nguyen, Jo-Anne Baltos, Trayder Thomas, Toan D Nguyen, Laura Lopez Munoz, Karen J Gregory, Paul J White, Patrick M Sexton, Arthur Christopoulos, Lauren T May
The adenosine A1 G protein-coupled receptor (A1AR) is an important therapeutic target implicated in a wide range of cardiovascular and neuronal disorders. Although it is well established that the A1AR orthosteric site is located within the receptor's transmembrane (TM) bundle, prior studies have implicated extracellular loop 2 (ECL2) as having a significant role in contributing to orthosteric ligand affinity and signaling for various G protein-coupled receptors (GPCRs). We thus performed extensive alanine scanning mutagenesis of the A1AR-ECL2 to explore the role of this domain on A1AR orthosteric ligand pharmacology...
September 28, 2016: Molecular Pharmacology
Anh Tn Nguyen, Elizabeth A Vecchio, Trayder Thomas, Toan D Nguyen, Luigi Aurelio, Peter J Scammells, Paul J White, Patrick M Sexton, Karen J Gregory, Lauren T May, Arthur Christopoulos
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders. However, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity and efficacy...
September 28, 2016: Molecular Pharmacology
Riley Edward Perszyk, John O DiRaddo, Katie L Strong, Chian-Ming Low, Kevin K Ogden, Alpa Khatri, Geoffrey A Vargish, Kenneth A Pelkey, Ludovic Tricoire, Dennis C Liotta, Yoland Smith, Chris J McBain, Stephen F Traynelis
NMDA receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus...
September 13, 2016: Molecular Pharmacology
(no author information available yet)
No abstract text is available yet for this article.
January 2017: Molecular Pharmacology
Jordan J Toutounchian, Jayaprakash Pagadala, Duane D Miller, Jerome Baudry, Frank Park, Edward Chaum, Charles R Yates
Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited...
January 2017: Molecular Pharmacology
J Daniel Hothersall, Dong Guo, Sunil Sarda, Robert J Sheppard, Hongming Chen, Wesley Keur, Michael J Waring, Adriaan P IJzerman, Stephen J Hill, Ian L Dale, Philip B Rawlins
The duration of action of adenosine A2A receptor (A2A) agonists is critical for their clinical efficacy, and we sought to better understand how this can be optimized. The in vitro temporal response profiles of a panel of A2A agonists were studied using cAMP assays in recombinantly (CHO) and endogenously (SH-SY5Y) expressing cells. Some agonists (e.g., 3cd; UK-432,097) but not others (e.g., 3ac; CGS-21680) demonstrated sustained wash-resistant agonism, where residual receptor activation continued after washout...
January 2017: Molecular Pharmacology
Matthew T Duvernay, Kayla J Temple, Jae G Maeng, Anna L Blobaum, Shaun R Stauffer, Craig W Lindsley, Heidi E Hamm
Human platelets display a unique dual receptor system for responding to its primary endogenous activator, α-thrombin. Because of the lack of efficacious antagonists, the field has relied on synthetic peptides and pepducins to describe protease-activated receptor PAR1 and PAR4 signaling. The precise contributions of each receptor have not been established in the context of thrombin. We took advantage of newly discovered PAR antagonists to contrast the contribution of PAR1 and PAR4 to thrombin-mediated activation of the platelet fibrin receptor (GPIIbIIIa)...
January 2017: Molecular Pharmacology
Hannah H Lee, Brenda F Leake, Richard B Kim, Richard H Ho
The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters...
January 2017: Molecular Pharmacology
Ana M Pajor, Cesar A de Oliveira, Kun Song, Kim Huard, Veerabahu Shanmugasundaram, Derek M Erion
The Na(+)/citrate transporter, NaCT (SLC13A5), is a therapeutic target for metabolic diseases. Citrate is an important signaling molecule that regulates the activity of lipid- and glucose-metabolizing enzymes in cells. Previous studies identified two compounds, PF-06649298 (compound 2: ) and PF-06678419 (compound 4: ), that inhibit human NaCT with high affinity, and one of the compounds demonstrated specificity relative to other SLC13 family members. Here we use molecular modeling and site-directed mutagenesis of hNaCT followed by transport characterization and cell-surface biotinylation to examine the residues involved in inhibitor binding and transport...
December 2016: Molecular Pharmacology
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