Abstract：
:In this study, we investigated the effects of single alanine substitutions of amino acid residues in the supposed ATP binding site of the human P2X3 receptor on the agonistic effect of nucleotide analogs. The wild-type and mutant receptors were expressed in HEK293 cells, and the nucleotide effects were measured by means of the whole-cell patch-clamp method. Modifications in the receptor binding site changed the concentration-response relationship, the current kinetics, and the recovery from desensitization during fast, pulsed, local agonist applications. On the basis of this fact, we were able to distinguish binding from other effects, such as gating/desensitization, by using a hidden Markov model that describes the complete channel behavior with a matrix of rate constants. The binding energies of the nucleotide analogs were calculated and compared with the binding energies of ATP at both the wild-type receptor and its alanine mutants. Changes in the binding energies caused by alterations in the receptor and/or agonist structures were concluded to be attributable to the preferential binding of certain structural constituents of ATP to certain amino acid moieties of the receptor. The results were also checked for consistency with a P2X3 homology model that we developed from the known zebrafish P2X4 crystal structure in the closed state. The functional data correlated well with the predictions of the agonist dockings to the structural model.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Riedel T,Wiese S,Leichsenring A,Illes Pdoi
10.1124/mol.112.077818subject
Has Abstractpub_date
2012-07-01 00:00:00pages
80-9issue
1eissn
0026-895Xissn
1521-0111pii
mol.112.077818journal_volume
82pub_type
杂志文章abstract：:delta-Opioid receptor (DOR) promoter exhibited a cell-type-specific expression pattern. Protein-DNA interactions in this promoter were identified by dimethyl sulfate in vivo footprinting analysis of NG108-15 cells, expressing endogenous DOR. Complete protection of the putative Sp1 cis-element and partial protection of...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.60.2.331
更新日期：2001-08-01 00:00:00
abstract：:Dehydroepiandrosterone (DHEA) is a peroxisome proliferating agent when administered in pharmacological dosages, but it has not been shown to function through the peroxisome proliferator-activated receptor in cell-based assays. Because members of the thyroid hormone/vitamins A and D nuclear receptor subfamily, includin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-02-01 00:00:00
abstract：:The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to acti...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2001-07-01 00:00:00
abstract：:The pharmacological preservation of bone in the ovariectomized rat by estrogen, selective estrogen receptor modulators (SERMs), and bisphosphonates has been well described. However, comprehensive molecular analysis of the effects of these pharmacologically diverse antiresorptive agents on gene expression in bone has n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.011478
更新日期：2005-11-01 00:00:00
abstract：:The dissociation constants (Kd values) of substance P (SP), physalaemin, kassinin, and SP analogues acting on SP receptors in guinea pig ileal longitudinal muscle strips were determined by the pharmacological procedures of Furchgott [Adv. Drug Res. 3:21-55 (1966)]. This method involves analysis of the concentration-re...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca 2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only micro receptors (GH3MOR cells), the micro receptor-specific ligand [D-Ala2,N-Me-Phe4,Gly5-o...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.63.1.89
更新日期：2003-01-01 00:00:00
abstract：:Metabolism of [3H]-(+/-)-trans-1,2-dihydroxy-1,2-dihydrobenz[a] anthracene by liver microsomes isolated from control, phenobarbital-treated, and 3-methylcholanthrene-treated Long-Evans rats and from 3-methylcholanthrene-treated Sprague-Dawley rats was examined. Liver microsomes from both control and phenobarbital-trea...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-07-01 00:00:00
abstract：:Several structurally related series of folate analogs were studied as substrates for mouse liver folylpolyglutamate synthetase (FPGS). A comparison of the kinetics of the interaction of this enzyme with folate analogs that contained the quinazoline ring in place of the pteridine ring with those of the analogous pterid...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1989-11-01 00:00:00
abstract：:The expression and molecular regulation of the cytochrome P450IA (P450IA) gene subfamily have been examined in rat hepatic tissue after treatment with pyridine. The microsomal ethoxyresorufin O-deethylase activity, which has been shown to be specific for the P450IA subfamily, was increased approximately 2- and 3.5-fol...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-07-01 00:00:00
abstract：:Neuroactive steroids have been postulated to cause anesthesia by binding to unique steroid recognition sites on gamma-aminobutyric acid (GABA) receptors and modulating GABA receptor function. Steroids interact with these sites diastereoselectively, but it is unknown whether steroid sites show enantioselectivity. To ad...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-12-01 00:00:00
abstract：:Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentra...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1986-04-01 00:00:00
abstract：:Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through beta(2)-adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both G(s) and G(i) proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, bu...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.5.1313
更新日期：2004-05-01 00:00:00
abstract：:TWIK-related K+ channel TREK1, a background leak K+ channel, has been strongly implicated as the target of several general and local anesthetics. Here, using the whole-cell and single-channel patch-clamp technique, we investigated the effect of lidocaine, a local anesthetic, on the human (h)TREK1 channel heterologousl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.056838
更新日期：2009-10-01 00:00:00
abstract：:Thymidine phosphorylase (TPase) is one of the key enzymes involved in the pyrimidine nucleoside salvage pathway. However, TPase also stimulates angiogenesis, and its expression correlates well with microvessel density and metastasis in a variety of human tumors. We have shown recently that 5'-O-trityl-inosine (KIN59) ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.021188
更新日期：2006-08-01 00:00:00
abstract：:We studied the mechanism by which the peptide omega-grammotoxin-SIA inhibits voltage-dependent calcium channels. Grammotoxin at concentrations of > 50 nM completely inhibited inward current carried by 2 mM barium through P-type channels in rat cerebellar Purkinje neurons when current was elicited by depolarizations up...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.52.6.1095
更新日期：1997-12-01 00:00:00
abstract：:The cytotoxic efficacy of antitumor drugs targeted at DNA topoisomerase II (topo II) in many cases varies in direct proportion to cellular topo II content. To investigate the transcriptional control of the predominant alpha form of topo II, the 5' flanking region of the human topo II alpha gene (positions -562 to +90)...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-04-01 00:00:00
abstract：:Resveratrol (RES), a natural plant polyphenol, has gained interest as a nontoxic chemopreventive agent capable of inducing tumor cell death in a variety of cancer types. However, the early molecular mechanisms of RES-induced apoptosis are not well defined. Using the human breast cancer cell lines MDA-MB-231 and MCF-7,...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.039040
更新日期：2007-12-01 00:00:00
abstract：:As noted previously, in N1E-115 neuroblastoma cells, carbamylcholine, a muscarinic cholinergic agonist, increased cGMP over 15-fold and decreased basal and prostaglandin E1 (PGE1)-stimulated cAMP content. In contrast to the stimulatory effects of PGE1 on cAMP, which were immediate, the carbamylcholine-induced decrease...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-08-01 00:00:00
abstract：:The deletion of Phe-508 (DeltaPhe508) constitutes the most prevalent of a number of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that cause cystic fibrosis (CF). This mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The b...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.055608
更新日期：2009-06-01 00:00:00
abstract：:Depolarization-induced 86Rb efflux, an index of K+ efflux, was developed by using mammalian cultured spinal cord neurons to study the effect of gamma aminobutyric acid (GABAB) receptor activation on Ca2(+)-activated K(+)-channels. The Ca2(+)-activated 86Rb efflux was obtained by using two methods. The first method uti...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-09-01 00:00:00
abstract：:Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-02-01 00:00:00
abstract：:The instability of the solubilized/purified form, the lack of catalytic activity of the stabilized, macrolide-complexed form, and the compromised catalytic activity of the decomplexed form of steroid-inducible cytochrome P450IIIA1 motivated further investigations of the substrate specificity of this isozyme. A major c...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-11-01 00:00:00
abstract：:2-Methyl-2-nitrosopropane (MNP) has long been known to undergo photochemical and thermal decomposition, generating di-tert-butyl nitroxide, in organic solvent. The present study was undertaken to demonstrate that MNP can be used as a caged-nitric oxide (NO), which can liberate NO upon illumination. Photolysis of MNP l...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-10-01 00:00:00
abstract：:Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available; is currently the third leading cause of cancer in developed countries; and is predicted to become the second deadliest cancer in the United States by 2030. Due to the marginal benefits of current standard chemotherapy, the...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.118.115444
更新日期：2019-07-01 00:00:00
abstract：:Eukaryotic cells assemble stress granules (SGs) when translation initiation is inhibited. Different cell signaling pathways regulate SG production. Particularly relevant to this process is 5'-AMP-activated protein kinase (AMPK), which functions as a stress sensor and is transiently activated by adverse physiologic con...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.105494
更新日期：2016-10-01 00:00:00
abstract：:We reported previously the formation of a glutathionyl conjugate of the active metabolite (AM) of clopidogrel and the covalent modification of a cysteinyl residue of human cytochrome P450 2B6 in a reconstituted system (Mol Pharmacol 80:839-847, 2011). In this work, we extended our studies of the metabolism of clopidog...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.079061
更新日期：2012-08-01 00:00:00
abstract：:Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
abstract：:Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, w...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.076471
更新日期：2012-03-01 00:00:00
abstract：:The vitamin D receptor (VDR) mediates vitamin D signaling in numerous physiological and pharmacological processes, including bone and calcium metabolism, cellular growth and differentiation, immunity, and cardiovascular function. Although transcriptional regulation by VDR has been investigated intensively, an understa...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.074138
更新日期：2011-12-01 00:00:00
