Abstract：
:The G-protein-coupled receptor GPR109A (HM74A/PUMA-G) has recently been shown to function as a receptor for nicotinic acid (niacin) and to mediate its antilipolytic effects. Nicotinic acid is able to strongly raise plasma levels of high-density lipoprotein cholesterol, a property that distinguishes nicotinic acid from other lipid-lowering drugs. To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid. We could identify Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) as amino acid residues critical for binding of nicotinic acid. Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors. Although Arg111 at TMH3 serves as the basic anchor point for the carboxylate ligands, the ring system of nicotinic acid is embedded between Trp91 at the junction TMH2/ECL1 and Phe276/Tyr284 at TMH7. The heterocyclic ring is also bound to Ser178 at ECL2 via an H-bond. These data will facilitate the design of new antidyslipidemic drugs acting via GPR109A.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Tunaru S,Lättig J,Kero J,Krause G,Offermanns Sdoi
10.1124/mol.105.015750keywords:
subject
Has Abstractpub_date
2005-11-01 00:00:00pages
1271-80issue
5eissn
0026-895Xissn
1521-0111pii
mol.105.015750journal_volume
68pub_type
杂志文章abstract：:Binding equilibria of 12 nonsteroidal, anti-inflammatory substances, salicylic acid, diflunisal, phenylbutazone, azapropazone, fenbufen, biphenylacetic acid, naproxen, flurbiprofen, ibuprofin, diclofenac, indomethacin, and benoxaprofen, to defatted human serum albumin has been investigated at 37 degrees, pH 7.4, in a ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1984-01-01 00:00:00
abstract：:The epithelial sodium channel (ENaC) is believed to represent the rate-limiting step for sodium absorption in the renal collecting duct. Consequently, ENaC is a central effector affecting systemic blood volume and pressure. Sodium and water transport are dysregulated in diabetes mellitus. Peroxisome proliferator-activ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.056911
更新日期：2009-12-01 00:00:00
abstract：:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found to activate protein kinases under cell- and nucleus-free conditions in isolated C57 mouse liver cytosol (100,000 x g supernatant). This action of TCDD was found to be aryl hydrocarbon receptor (AHR) dependent, concentration dependent, and inhibited by genistein, a t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.4.667
更新日期：1997-10-01 00:00:00
abstract：:Because cytotoxicity by an alkylating agent such as N-methyl-N'-nitrosoguanidine is markedly increased in adenine methylase-deficient dam-3 Escherichia coli, it was of interest to assess whether mismatch repair was similarly important in the repair of DNA damage induced by cis-diamminedichloroplatinum(II) (CDDP). The ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-07-01 00:00:00
abstract：:The P2Y(1) receptor is responsible for the initiation of platelet aggregation in response to ADP and plays a key role in thrombosis. Although this receptor is expressed early in the platelet lineage, the regulation of its expression during megakaryocyte differentiation is unknown. In the mouse megakaryocytic cell line...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.60.5.1112
更新日期：2001-11-01 00:00:00
abstract：:A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1997-03-01 00:00:00
abstract：:There is no approved means to prevent the toxic actions of cocaine. Cocaine esterase (CocE) is found in a rhodococcal strain of bacteria that grows in the rhizosphere soil around the coca plant and has been found to hydrolyze cocaine in vitro. The esteratic activity of CocE (0.1-1.0 mg, i.v.) was characterized and con...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.025999
更新日期：2006-12-01 00:00:00
abstract：:Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxacin, enoxacin, and pipemidic acid), known to be gamma-aminobutyric acid (GABA) antagonists, fully reversed the inhibitory effect of GABA on [35S]t-butylbicyclophosphorothionate ([35S] TBPS) binding to rat brain membranes in vitro. Twelve indomethacin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-05-01 00:00:00
abstract：:Recently we demonstrated that the effects of beta 2-adrenoceptor (AR) stimulation to augment Ca2+ current (ICa), cytosolic Ca2+ (Cai) transients, and contractility in rat ventricular myocytes are largely dissociated from its effect to increase cellular cAMP levels. This result suggested that beta 2ARs might be coupled...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-02-01 00:00:00
abstract：:Receptors from distant species may have conserved functions despite significant differences in protein sequences. Whereas the noncritical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant spe...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.074500
更新日期：2011-11-01 00:00:00
abstract：:Angiotensin II (AII) stimulates rapid increases in cytosolic Ca2+ concentrations in Xenopus laevis oocytes after binding to specific receptors located in the surrounding follicular cells. In follicular oocytes, the peptide AII receptor antagonists saralasin (IC50 = 25 nM) and CGP 42112A (IC50 = 400 nM) were orders of ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-02-01 00:00:00
abstract：:Anthracyclines are effective anticancer agents. However, their use is limited by cardiotoxicity, an effect linked to their ability to chelate iron and to perturb iron metabolism (Mol Pharmacol 68:261-271, 2005). These effects on iron-trafficking remain poorly understood, but they are important to decipher because trea...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.041335
更新日期：2008-03-01 00:00:00
abstract：:The binding of two anthranilic acid derivatives, glafenic and floctafenic acids, to human erythrocytes and plasma proteins has been investigated in vitro by equilibrium dialysis. Despite their close chemical structures it was shown that the binding of the two compounds to serum albumin, lipoproteins, and erythrocytes ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-03-01 00:00:00
abstract：:Using an oligonucleotide based on the sequence of a porcine brain muscarinic receptor cDNA, we recently cloned four distinct muscarinic receptors from the rat and human genomes. In the present study we transfected the rat homolog of the porcine brain muscarinic receptor cDNA into A9 L cells using a mammalian expressio...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-10-01 00:00:00
abstract：:Several 2-amino-3-benzoylthiophenes were found to increase the binding of [3H]N6-cyclohexyladenosine to A1 adenosine receptors in rat brain membranes. Concentration-response curves were bell-shaped, with up to 45% stimulation of binding at 10 microM followed by inhibition at higher concentrations. Because these compou...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-12-01 00:00:00
abstract：:The aim of this study was to clarify the mechanism by which cytochrome P450 (P450)-mediated catalytic activity is decreased following interferon (IFN) administration. Microsomal steroid hydroxylation was assessed to test the hypothesis that IFN selectively decreases the activities of individual P450 isozymes in male r...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:The binding of [3H]quinuclidinyl benzilate ([3H]QNB) to cardiac muscarinic receptors was inhibited not only by classical muscarinic antagonists but also by nicotinic blocking agents and inhibitors of acetylcholinesterase. Gallamine, pancuronium, ambenonium, and decamethonium were the most potent of these agents examin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-07-01 00:00:00
abstract：:The Notch family consists of four highly conserved transmembrane receptors. The release of the active intracellular domain requires the enzymatic activity of γ-secretase. Notch is involved in embryonic development and in many physiologic processes of normal cells, in which it regulates growth, apoptosis, and different...
journal_title：Molecular pharmacology
pub_type： 杂志文章,评审
doi：10.1124/molpharm.120.000006
更新日期：2020-11-01 00:00:00
abstract：:In rat pancreatic zymogen granules (ZG), an ATP-sensitive K(+) conductance and a Cl(-) conductance have been characterized that are inversely regulated by an approximately 65-kDa multidrug resistance P-glycoprotein (mdr1) gene product. In search of a label for purification of this protein, we found that the dihydropyr...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-02-01 00:00:00
abstract：:Nitric oxide (NO) promotes retinal and choroidal neovascularization, although different isoforms of nitric-oxide synthetase (NOS) are critical in each. Deficiency of endothelial NOS (eNOS) suppresses retinal but not choroidal neovascularization, whereas deficiency of neuronal NOS (nNOS) or inducible NOS (iNOS) suppres...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.62.3.539
更新日期：2002-09-01 00:00:00
abstract：:Sulfation, catalyzed by members of the sulfotransferase (SULT) superfamily, exerts considerable influence over the biological activity of numerous endogenous and xenobiotic chemicals. In humans, catecholamines such as dopamine are extensively sulfated, and a SULT isoform (SULT1A3 or the monoamine-sulfating form of phe...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.6.942
更新日期：1998-12-01 00:00:00
abstract：:It has long been believed that the cortical actin cytoskeleton plays an important role in regulating the secretion of hormones and neurotransmitters. In this study, we investigated the control of actin dynamics in primary neuroendocrine cells and determined the relationship of actin dynamics to various components of t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.008474
更新日期：2005-04-01 00:00:00
abstract：:We show here that arsenite (As(3+)) elicits multiple effects on gene control, such as the interruption of cell cycle control by initiating G(2)/M arrest as well as inhibiting the aryl hydrocarbon (Ah) receptor-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible expression of CYP1A1. This raises the question ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.006130
更新日期：2005-04-01 00:00:00
abstract：:The sulfoconjugation of tyrosyl residues is a widespread post-translational modification of biologically active proteins and peptides. The rat liver Golgi enzyme tyrosylprotein sulfotransferase has previously been shown to catalyze the transfer of a sulfate moiety from 5'-phosphoadenosine-3'-phosphosulfate to the synt...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-10-01 00:00:00
abstract：:Anthracyclines are potent anticancer agents, but their use is limited by cardiotoxicity at high cumulative doses. The mechanisms involved in anthracycline-mediated cardiotoxicity are still poorly understood, but numerous investigations have indicated a role for iron in this process. Our previous studies using neoplast...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.1.181
更新日期：2004-01-01 00:00:00
abstract：:The interaction between some examples of mononuclear and binuclear DNA-intercalating antitumor agents and alpha- and beta-adrenoceptors has been studied using radioligand-binding assays. Competition for 125I-BE 2254, [3H]rauwolscine, and (-)-[3H]dihydroalprenolol binding was used to assess affinity for alpha 1-, alpha...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-04-01 00:00:00
abstract：:Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFRs) are ubiquitously expressed in the mammalian central nervous system, where they exert trophic actions on both neuronal and glial cells. However, the acute actions of PDGF on synaptic transmission are unknown. We report a novel regulatory action of PDGF/P...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-12-01 00:00:00
abstract：:The response of myeloid leukemia cells to treatment with 1-beta-D-arabinofuranosylcytosine (ara-C) includes activation of the c-Abl protein tyrosine kinase and the stress-activated protein kinase (SAPK). The present studies demonstrate that treatment of human U-937 leukemia cells with ara-C is associated with transloc...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.6.1489
更新日期：2002-06-01 00:00:00
abstract：:The in vitro binding of [3H]LY354740, the first high affinity group II-selective metabotropic glutamate (mGlu) receptor radioligand, was characterized in rat cortical, hippocampal, and thalamic membranes as well as in rat brain sections. [3H]LY354740 binding was saturable in all regions investigated. Nonspecific bindi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1998-02-01 00:00:00
abstract：:In a previous report we described the use of flunitrazepam as a photoaffinity label to monitor the turnover of the gamma-aminobutyric acid/benzodiazepine receptor complex in primary brain and spinal cord cell cultures [Science (Wash. D. C.) 226:857-860 (1984)]. In the present communication we have extended our studies...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-09-01 00:00:00
