Abstract:
:Gamma-aminobutyric acid type A receptors (GABA(A) receptors) are ligand-gated chloride channels that play a central role in signal transmission within the mammalian central nervous system. Compounds that modulate specific GABA(A) receptor subtypes containing the delta-subunit are scarce but would be valuable research tools and starting points for potential therapeutic agents. Here we report a class of dihydropyrimidinone (DHPM) heterocycles that preferentially potentiate peak currents of recombinant GABA(A) receptor subtypes containing the delta-subunit expressed in HEK293T cells. Using the three-component Biginelli reaction, 13 DHPMs with structural features similar to those of the barbiturate phenobarbital were synthesized; one DHPM used (monastrol) is commercially available. An up to approximately 3-fold increase in the current from recombinant alpha1beta2delta receptors was observed with the DHPM compound JM-II-43A or monastrol when co-applied with saturating GABA concentrations, similar to the current potentiation observed with the nonselective potentiating compounds phenobarbital and tracazolate. No agonist activity was observed for the DHPMs at the concentrations tested. A kinetic model was used in conjunction with dose-dependent measurements to calculate apparent dissociation constant values for JM-II-43A (400 muM) and monastrol (200 microM) at saturating GABA concentrations. We examined recombinant receptors composed of combinations of subunits alpha1, alpha4, alpha5, alpha6, beta2, beta3, gamma2L, and delta with JM-II-43A to demonstrate the preference for potentiation of delta-subunit-containing receptors. Lastly, reduced currents from receptors containing the mutated delta(E177A) subunit, described by Dibbens et al. [(2004) Hum. Mol. Genet. 13, 1315-1319] as a heritable susceptibility allele for generalized epilepsy with febrile seizures plus, are also potentiated by these DHPMs.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Lewis RW,Mabry J,Polisar JG,Eagen KP,Ganem B,Hess GPdoi
10.1021/bi100119tsubject
Has Abstractpub_date
2010-06-15 00:00:00pages
4841-51issue
23eissn
0006-2960issn
1520-4995journal_volume
49pub_type
杂志文章相关文献
BIOCHEMISTRY文献大全abstract::Infrared spectroscopy has been used to monitor residual ordered structure in the denatured state of wild-type and two mutants of iso-1-cytochrome c. The technique used involves a careful digital subtraction procedure that removes spectral contributions from buffer, water vapor, and the denaturant guanidine hydrochlori...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00175a008
更新日期:1994-03-08 00:00:00
abstract::Among the 118 genes upregulated by Pseudomonas aeruginosa in response to iron starvation [Ochsner, U. A., Wilderman, P. J., Vasil, A. I., and Vasil, M. L. (2002) Mol. Microbiol. 45, 1277-1287], we focused on the products of the two genes encoding electron transfer proteins, as a means of identifying the redox partners...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi7013135
更新日期:2007-10-30 00:00:00
abstract::Candida albicans drug resistance protein 1 (Cdr1p), an ATP-dependent drug efflux pump, contributes to multidrug resistance in Candida-infected immunocompromised patients. Previous cell-based assays suggested that Cdr1p also acts as a phospholipid translocator. To investigate this, we reconstituted purified Cdr1p into ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi700453e
更新日期:2007-10-30 00:00:00
abstract::The removal of cylclobutane pyrimidine dimers from cellular DNA occurs preferentially in actively transcribed genes of cells subjected to ultraviolet radiation. In contrast, reports concerning the transcription-dependent repair of N-methylpurines formed in cellular DNA following exposure to methylating agents are quit...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00005a037
更新日期:1995-02-07 00:00:00
abstract::The actin depolymerizing factor (ADF)/cofilins are an essential group of proteins that are important regulators of actin filament turnover in vivo. Although protists and yeasts express only a single member of this family, metazoans express two or more members in many cell types. In cells expressing both ADF and cofili...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi049797n
更新日期:2004-06-08 00:00:00
abstract::Aminoacyl-tRNA synthetases contain one or three Mg(2+) ions in their catalytic sites. In addition to their role in ATP binding, these ions are presumed to play a role in catalysis by increasing the electropositivity of the alpha-phosphate and stabilizing the pentavalent transition state. In the class II aaRS, two high...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi049617+
更新日期:2004-06-08 00:00:00
abstract::The prothrombinase complex assembles through reversible interactions between factor Xa, factor Va and acidic phospholipid-containing membranes in the presence of calcium ions. This complex catalyses the conversion of prothrombin to thrombin through two proteolytic steps. We have used prethrombin 2 as a substrate analo...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi9623993
更新日期:1997-03-18 00:00:00
abstract::X-ray structural information provides the opportunity to explore quantitatively the relation between the microenvironments of heme proteins and their redox potentials. This can be done by considering the protein as a "solvent" for its redox center and calculating the difference between the electrostatic energy of the ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00355a035
更新日期:1986-04-08 00:00:00
abstract::We have assayed the cross-linking of oligonucleotides containing repeated mitomycin-reactive CpG sites in order to assess the factors that enhance activation of the carbamoyl function at C10, yielding efficient mitomycin cross-linking. Drugs studied include mitomycin C (MC), N-methylmitomycin A (NMA), and the aziridin...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00439a049
更新日期:1989-06-27 00:00:00
abstract::To better understand origin recognition and initiation of DNA replication, we have examined by NMR complexes formed between the origin-binding domain of SV40 T antigen (T-ag-obd), the initiator protein of the SV40 virus, and cognate and noncognate DNA oligomers. The results reveal two structural effects associated wit...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi030228+
更新日期:2004-06-08 00:00:00
abstract::alpha-Conotoxin GI is a snail toxin protein consisting of 13 amino acids cross-linked by 2 intramolecular disulfide bridges. This toxin is an antagonist of acetylcholine receptors. The native sequence has been synthesized, along with nine additional variants in which non-cysteine residues are replaced by alanine or th...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00111a021
更新日期:1991-11-26 00:00:00
abstract::Mutagenesis and cross-linking measurements have identified specific contact interactions between the cytosolic and the transmembrane sequences of phospholamban (PLB) and the Ca-ATPase, and in conjunction with the high-resolution structures of PLB and the Ca-ATPase, have been used to construct models of the PLB-ATPase ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi035424v
更新日期:2004-01-20 00:00:00
abstract::The role of ion channels in cell physiology is regulated by processes occurring after protein biosynthesis, which are critical for both channel function and targeting of channels to appropriate cell compartments. Here we apply biochemical and electrophysiological methods to investigate the role of the high-conductance...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi050527u
更新日期:2005-08-02 00:00:00
abstract::Light-driven outward sodium-pumping rhodopsin (NaR) was recently found in marine bacteria. Krokinobacter eikastus rhodopsin 2 (KR2) actively transports sodium and lithium ions in NaCl and LiCl, respectively, while it pumps protons in KCl. NaR has a conserved NDQ (N112, D116, and Q123 in KR2) motif, and previous studie...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/acs.biochem.6b00741
更新日期:2016-10-18 00:00:00
abstract::Information on the secondary structure and interactions of RNA is important to understand the biological function of RNA as well as in applying RNA as a tool for therapeutic purposes. Recently, the isoenergetic microarray mapping method was developed to improve the prediction of RNA secondary structure. Herein, for th...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi200463p
更新日期:2011-09-06 00:00:00
abstract::The functional diversity of small GTP-binding proteins (G proteins) and their ability to function as molecular switches are based on their interactions with many different proteins. A wealth of structural data has revealed that their partners are often unrelated to each other in sequence and structure, but their bindi...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi049630u
更新日期:2004-06-08 00:00:00
abstract::The structure and dynamic properties of the C-terminal region of the human class alpha glutathione transferase A1-1 have been investigated with high-resolution NMR methods. On the basis of crystallographic and fluorescence measurements, this 13-residue segment of the enzyme is presumed to be disordered in the unligand...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi0363329
更新日期:2004-06-15 00:00:00
abstract::We have sought to determine the role of histone H2A phosphorylation in chromatin by examining the distribution of the phosphorylated and unphosphorylated forms of this core histone within the nuclei of mouse and human cells. At any time, only about 15% of the H2A of whole chromatin is in the phosphorylated form, and i...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00539a021
更新日期:1982-05-11 00:00:00
abstract::The potassium form of d(CGCGAATTCGCG) solved by X-ray diffraction to 1.75 A resolution indicates that monovalent cations penetrate the primary and secondary layers of the "spine of hydration". Both the sodium [Shui, X., McFail-Isom, L., Hu, G. G., and Williams, L. D. (1998) Biochemistry 37, 8341-8355] and the potassiu...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi982063o
更新日期:1998-12-01 00:00:00
abstract::We have examined the structure of newly repaired regions of chromatin in intact and permeabilized human cells following exposure to bleomycin (BLM). The average repair patch size (in permeabilized cells) was six to nine bases, following doses of 1-25 micrograms/mL BLM, and greater than 80% of the total repair synthesi...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00484a020
更新日期:1990-08-14 00:00:00
abstract::The cardiac and skeletal muscle sarcoplasmic reticulum ryanodine receptor Ca(2+) release channels contain thiols that are potential targets of endogenously produced reactive oxygen and nitrogen intermediates. Previously, we showed that the skeletal muscle ryanodine receptor (RyR1) has O(2)-sensitive thiols; only when ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi8012627
更新日期:2008-12-30 00:00:00
abstract::A number of nucleosides related to S-adenosylmethionine were tested for their inhibitory action on three enzymes involved in the biosynthesis of polyamines. The particular objective of the experiments was to determine whether any of the compounds could be used as selective inhibitors of the synthesis of spermine by sp...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00362a016
更新日期:1986-07-15 00:00:00
abstract::Sedimentation in a preparative ultracentrifuge was used to determine the affinity of heavy meromyosin, HMM, for regulated actin, F-actin plus troponin-tropomyosin, in the presence of MgATP at pH 7.0, 20 degrees C, and mu = 18 mM. HMM was prepared from vertebrate striated muscle myosin by a mild chymotryptic digestion....
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00275a003
更新日期:1983-03-15 00:00:00
abstract::Kinetic studies of reactions between fluorescein and antifluorescein antibody produced during early, intermediate, and late stages of the immune response have been carried out utilizing both fluorescence intensity and polarization measurements in the static (time constant similar to 5 sec) and in the stopped-flow mode...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00688a009
更新日期:1975-08-26 00:00:00
abstract::31P NMR measurements were made (at 121.5 MHz and 5 degrees C) on enzyme-bound substrate complexes of 3-phosphoglycerate kinase in order to address three questions pertaining to (i) the integrity of the enzyme-substrate complexes with Mg(II) in the presence of sulfate concentrations typical of those used for crystalliz...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00415a027
更新日期:1988-07-26 00:00:00
abstract::We have examined proteins containing the DNA-binding domain of c-Myb with biophysical methods. This DNA-binding domain consists of three imperfect repeats (R1, R2, and R3) conserved among many species. Our results indicate that the DNA-binding domain forms unspecific and specific complexes with oligodeoxynucleotides. ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00252a026
更新日期:1994-12-06 00:00:00
abstract::Membrane proteins are embedded in a lipid bilayer and maintain strong interactions with lipid molecules. Tightly bound lipids are responsible for vertical positioning and integration of proteins in the membrane and for assembly of multisubunit complexes and occasionally act as substrates. In this work we present the l...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi900545e
更新日期:2009-10-20 00:00:00
abstract::Kirromycin and related antibiotics inhibit protein synthesis in bacteria by acting on elongation factor Tu (EF-Tu). We have studied the effects of N-methylkirromycin (aurodox) on some molecular properties of this protein. The binding of the antibiotic causes a dramatic variation in the protein fluorescence emission sp...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00443a046
更新日期:1989-08-22 00:00:00
abstract::The binding of rabbit globin mRNA to the 25-kDa cap binding protein eIF-4E from human erythrocytes was found to be 5.3-fold stronger than the binding of the cap analogue m7GpppG to eIF-4E [Gross et al. (1990) Biochemistry 29, 5008-5012]. In order to investigate whether this effect is due to the longer sequence of nucl...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00120a020
更新日期:1992-02-11 00:00:00
abstract::Site-directed spin labeling (SDSL), the site-specific incorporation of nitroxide spin-labels into a protein, has allowed us to investigate ligand-induced conformational changes in the ligand-binding domain of human estrogen receptor alpha (hERalpha-LBD). EPR (electron paramagnetic resonance) spectroscopy of the nitrox...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi035566p
更新日期:2004-02-24 00:00:00