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The mouse ortholog of NEIL3 is a functional DNA glycosylase in vitro and in vivo.
Liu M, Bandaru V, Bond JP, Jaruga P, Zhao X, Christov PP, Burrows CJ, Rizzo CJ, Dizdaroglu M, Wallace SS
(2010) Proc Natl Acad Sci U S A 107: 4925-30
MeSH Terms: Amino Acid Sequence, Animals, DNA, DNA Damage, DNA Glycosylases, Endodeoxyribonucleases, Escherichia coli, Gamma Rays, Guanidines, Guanosine, Hydantoins, Kinetics, Mice, Molecular Sequence Data, Mutation, Pyrimidines, Schiff Bases, Sequence Alignment, Sequence Homology, Amino Acid, Spiro Compounds, Substrate Specificity, Valine
Show Abstract · Added January 7, 2016
To protect cells from oxidative DNA damage and mutagenesis, organisms possess multiple glycosylases to recognize the damaged bases and to initiate the Base Excision Repair pathway. Three DNA glycosylases have been identified in mammals that are homologous to the Escherichia coli Fpg and Nei proteins, Neil1, Neil2, and Neil3. Neil1 and Neil2 in human and mouse have been well characterized while the properties of the Neil3 protein remain to be elucidated. In this study, we report the characterization of Mus musculus (house mouse) Neil3 (MmuNeil3) as an active DNA glycosylase both in vitro and in vivo. In duplex DNA, MmuNeil3 recognizes the oxidized purines, spiroiminodihydantoin (Sp), guanidinohydantoin (Gh), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 4,6-diamino- 5-formamidopyrimidine (FapyA), but not 8-oxo-7,8-dihydroguanine (8-oxoG). Interestingly, MmuNeil3 prefers lesions in single-stranded DNA and in bubble structures. In contrast to other members of the family that use the N-terminal proline as the nucleophile, MmuNeil3 forms a Schiff base intermediate via its N-terminal valine. We expressed the glycosylase domain of MmuNeil3 (MmuNeil3Delta324) in an Escherichia coli triple mutant lacking Fpg, Nei, and MutY glycosylase activities and showed that MmuNeil3 greatly reduced both the spontaneous mutation frequency and the level of FapyG in the DNA, suggesting that Neil3 plays a role in repairing FapyG in vivo.
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22 MeSH Terms
Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function.
Smith JP, Weller S, Johnson B, Nicotera J, Luther JM, Haas DW
(2010) Antimicrob Agents Chemother 54: 1146-51
MeSH Terms: Acyclovir, Adult, Aged, Antiviral Agents, Chronic Disease, Female, Guanine, Humans, Kidney, Kidney Diseases, Kidney Function Tests, Male, Medical Futility, Middle Aged, Prodrugs, Valacyclovir, Valine, Young Adult
Show Abstract · Added August 21, 2013
Valacyclovir, the L-valyl ester prodrug of acyclovir (ACV), is widely prescribed to treat infections caused by varicella-zoster virus or herpes simplex virus. Rarely, treatment is complicated by reversible neuropsychiatric symptoms. By mechanisms not fully understood, this occurs more frequently in the setting of renal impairment. We characterized the steady-state pharmacokinetics of ACV and its metabolites 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8-hydroxy-acyclovir (8-OH-ACV) in cerebrospinal fluid (CSF) and the systemic circulation. We administered multiple doses of high-dose valacyclovir to 6 subjects with normal renal function and 3 subjects with chronic renal impairment (creatinine clearance [CrCl], approximately 15 to 30 ml/min). Dosages were 2,000 mg every 6 h and 1,500 mg every 12 h, respectively. Indwelling intrathecal catheters allowed serial CSF sampling throughout the dosing interval. The average steady-state concentrations of acyclovir, CMMG, and 8-OH-ACV were greater in both the systemic circulation and the CSF among subjects with impaired renal function than among subjects with normal renal function. However, the CSF penetration of each analyte, reflected by the CSF-to-plasma area under the concentration-time curve over the 6- or 12-h dosing interval (AUC(tau)) ratio, did not differ based on renal function. Renal impairment does not alter the propensity for ACV or its metabolites to distribute to the CSF, but the higher concentrations in the systemic circulation, as a result of reduced elimination, are associated with proportionally higher concentrations in CSF.
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18 MeSH Terms
Regulation of stargazin synaptic trafficking by C-terminal PDZ ligand phosphorylation in bidirectional synaptic plasticity.
Stein EL, Chetkovich DM
(2010) J Neurochem 113: 42-53
MeSH Terms: Animals, Calcium Channels, Cells, Cultured, Chlorocebus aethiops, Cyclic AMP-Dependent Protein Kinases, Disks Large Homolog 4 Protein, Embryo, Mammalian, Excitatory Amino Acid Antagonists, Hippocampus, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Long-Term Potentiation, Long-Term Synaptic Depression, Membrane Proteins, Methoxyhydroxyphenylglycol, Mitogen-Activated Protein Kinases, Mutagenesis, Neuronal Plasticity, Neurons, PDZ Domains, Phosphorylation, Protein Transport, Rats, Threonine, Transfection, Valine
Show Abstract · Added April 2, 2019
Stargazin is a transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein that controls the surface and synaptic expression of AMPA-type glutamate receptors (AMPARs). Synaptic anchoring of AMPARs is influenced by the interaction between stargazin's C-terminal post-synaptic density-95 (PSD-95)/discs large/zona occludens-1 (PDZ) ligand and the synaptic scaffolding protein PSD-95. Phosphorylation of the stargazin PDZ ligand by protein kinase A (PKA) disrupts stargazin's interaction with PSD-95, but whether this phosphorylation plays a role in activity-dependent regulation of stargazin/AMPAR synaptic trafficking is unknown. Here, we show that stargazin is phosphorylated within the PDZ ligand at threonine residue 321 (T321) by mitogen-activated protein kinases (MAPKs) as well as PKA. By expressing constructs that selectively block T321 phosphorylation by either PKA or MAPKs, we show that stargazin T321 phosphorylation is required for activity-dependent changes in stargazin synaptic clustering in dissociated rat hippocampal neuron cultures. Specifically, we find that mutations that block stargazin T321 phosphorylation by PKA prevent activity-dependent increases in stargazin synaptic clustering, whereas a point mutant that blocks MAPK phosphorylation of T321 prevents activity-dependent decreases in stargazin synaptic clustering. Taken together, our studies implicate phosphorylation of stargazin T321 by PKA and MAPKs in bidirectional control of stargazin/AMPAR synaptic clustering during synaptic plasticity.
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26 MeSH Terms
Anomalous dopamine release associated with a human dopamine transporter coding variant.
Mazei-Robison MS, Bowton E, Holy M, Schmudermaier M, Freissmuth M, Sitte HH, Galli A, Blakely RD
(2008) J Neurosci 28: 7040-6
MeSH Terms: Alanine, Amphetamine, Analysis of Variance, Biotinylation, Cell Line, Transformed, Dopamine, Dopamine Plasma Membrane Transport Proteins, Dopamine Uptake Inhibitors, Humans, Membrane Potentials, Methylphenidate, Mutation, Patch-Clamp Techniques, Protein Transport, Sodium, Transfection, Valine
Show Abstract · Added December 10, 2013
Dopamine (DA) signaling at synapses is tightly coordinated through opposing mechanisms of vesicular fusion-mediated DA release and transporter-mediated DA clearance. Altered brain DA signaling is suspected to underlie multiple brain disorders, including schizophrenia, Parkinson's disease, bipolar disorder, and attention-deficit hyperactivity disorder (ADHD). We identified a pedigree containing two male children diagnosed with ADHD who share a rare human DA transporter (DAT; SLC6A3) coding variant, Ala559Val. Among >1000 control and affected subjects, the Val559 variant has only been isolated once previously, in a female subject with bipolar disorder. Although hDAT Ala559Val supports normal DAT protein and cell surface expression, as well as normal DA uptake, the variant exhibits anomalous DA efflux from DA-loaded cells. We also demonstrate that hDAT Ala599Val exhibits increased sensitivity to intracellular Na(+), but not intracellular DA, and displays exaggerated DA efflux at depolarized potentials. Remarkably, the two most common ADHD medications, amphetamine and methylphenidate, both block hDAT Ala559Val-mediated DA efflux, whereas these drugs have opposite actions at wild-type hDAT. Our findings reveal that DA efflux, typically associated with amphetamine-like psychostimulants, can be produced through a heritable change in hDAT structure. Because multiple gene products are known to coordinate to support amphetamine-mediated DA efflux, the properties of hDAT Ala559Val may have broader significance in identifying a new mechanism through which DA signaling disorders arise. Additionally, they suggest that block of inappropriate neurotransmitter efflux may be an unsuspected mechanism supporting the therapeutic actions of existing transporter-directed medications.
1 Communities
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17 MeSH Terms
Acetylation of N-terminal valine of glycine N-methyltransferase affects enzyme inhibition by folate.
Luka Z, Loukachevitch LV, Wagner C
(2008) Biochim Biophys Acta 1784: 1342-6
MeSH Terms: Acetylation, Allosteric Regulation, Animals, Enzyme Inhibitors, Folic Acid, Glycine N-Methyltransferase, In Vitro Techniques, Kinetics, Liver, Models, Molecular, Protein Conformation, Rats, Recombinant Proteins, Valine
Show Abstract · Added January 20, 2015
Native liver glycine N-methyltransferase (GNMT) is N-acetylated while the recombinant enzyme is not. We show here that acetylation of the N-terminal valine affects several kinetic parameters of the enzyme. Glycine N-methyltransferase is a regulatory enzyme mediating the availability of methyl groups by virtue of being inhibited by folate. N-acetylation does not affect the overall structure of the protein and does not affect basal enzyme activity of GNMT. Binding of both the mono- and pentaglutamate forms of 5-methyltetrahydrofolate is the same for the acetylated and non-acetylated forms of the enzyme, however the pentaglutamate form is bound more tightly than the monoglutamate form in both cases. Although binding of the folates is similar for the acetylated and non-acetylated forms of the enzyme, inhibition of enzyme activity differs significantly. The native, N-acetylated form of the enzyme shows 50% inhibition at 1.3 microM concentration of the pentaglutamate while the recombinant non-acetylated form shows 50% inhibition at 590 microM. In addition, the binding of folate results in cooperativity of the substrate S-adenosylmethionine (AdoMet), with a Hill coefficient of 1.5 for 5-methyltetrahydrofolate pentaglutamate.
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14 MeSH Terms
N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) acts through a novel site as a positive allosteric modulator of group 1 metabotropic glutamate receptors.
Chen Y, Goudet C, Pin JP, Conn PJ
(2008) Mol Pharmacol 73: 909-18
MeSH Terms: Allosteric Regulation, Allosteric Site, Amino Acid Sequence, Amino Acid Substitution, Animals, Astrocytes, Benzamides, Calcium, Cell Culture Techniques, Cell Line, Cells, Cultured, Cerebral Cortex, Cricetinae, Dose-Response Relationship, Drug, Humans, Kidney, Ligands, Molecular Sequence Data, Molecular Structure, Protein Structure, Tertiary, Radioligand Assay, Rats, Receptors, Metabotropic Glutamate, Sequence Homology, Amino Acid, Transfection, Valine
Show Abstract · Added February 19, 2015
Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29- and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.
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26 MeSH Terms
ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy.
Michaelides M, Chen LL, Brantley MA, Andorf JL, Isaak EM, Jenkins SA, Holder GE, Bird AC, Stone EM, Webster AR
(2007) Br J Ophthalmol 91: 1650-5
MeSH Terms: ATP-Binding Cassette Transporters, Adolescent, Adult, Aged, Alanine, Alleles, Cohort Studies, Female, Glutamic Acid, Glycine, Humans, Macula Lutea, Male, Middle Aged, Mutation, Mutation, Missense, Pedigree, Phenotype, Retinal Diseases, Siblings, Valine
Show Abstract · Added December 10, 2013
AIM - To determine the frequency and nature of mutations in the gene ABCA4 in a cohort of patients with bull's-eye maculopathy (BEM).
METHODS - A panel of 49 subjects (comprising 40 probands/families, 7 sibling pairs and a set of three sibs) with BEM, not attributable to toxic causes, was ascertained. Blood samples from each patient were used to extract genomic DNA, with subsequent mutation screening of the entire coding sequence of ABCA4, using single-strand conformational polymorphism (SSCP) analysis and direct sequencing.
RESULTS - Fourteen probands (35%) were found to have a potentially disease-causing ABCA4 sequence variant on at least one allele. Three patients had a Gly1961Glu missense mutation, the most common variant in Stargardt disease (STGD), with 2 of these subjects having a macular dystrophy (MD) phenotype and a second ABCA4 variant previously associated with STGD. The second most common STGD mutation, Ala1038Val, was seen in one patient with cone-rod dystrophy (CORD). Five novel ABCA4 variants were detected. Two sibships were identified with a similar intra-familial phenotype but discordant ABCA4 variants.
CONCLUSIONS - Variations in the ABCA4 gene are common in BEM. Two sibships showed discordant ABCA4 variants. One of these sibships illustrates that ABCA4 variants can be identified in families that have another molecular cause for their disease, due to the high prevalence of ABCA4 disease alleles in the population. The discordance evident in the second sibship may yet also be a chance finding in families with macular disease of another genetic cause, or it may represent a complex mode of inheritance determined/modified by the combination of ABCA4 alleles.
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21 MeSH Terms
Bradykinin B(2) receptor does not contribute to blood pressure lowering during AT(1) receptor blockade.
LeFebvre J, Shintani A, Gebretsadik T, Petro JR, Murphey LJ, Brown NJ
(2007) J Pharmacol Exp Ther 320: 1261-7
MeSH Terms: Adult, Angiotensin II Type 1 Receptor Blockers, Blood Pressure, Bradykinin, Bradykinin B2 Receptor Antagonists, Cross-Over Studies, Cyclic GMP, Diet, Sodium-Restricted, Female, Heart Rate, Humans, Hypertension, Male, Receptor, Bradykinin B2, Renin, Sodium, Tetrazoles, Valine, Valsartan
Show Abstract · Added December 10, 2013
This study tested the hypothesis that endogenous bradykinin contributes to the effects of angiotensin AT(1) receptor blockade in humans. The effect of the bradykinin B(2) receptor antagonist d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-Oic-Arg (HOE-140) (18 microg/kg/h i.v. for 6 h) on hemodynamic and endocrine responses to acute and chronic (1-month) treatment with valsartan (160 mg/day) was determined in 13 normotensive and 12 hypertensive salt-deplete subjects. Acute valsartan increased plasma renin activity (PRA) from 5.3 +/- 9.9 to 15.6 +/- 19.8 ng of angiotensin (Ang) I/ml/h (P < 0.001) and decreased aldosterone from 18.3 +/- 10.5 to 12.0 +/- 9.6 ng/dl (P < 0.001). Chronic valsartan significantly increased baseline PRA (10.5 +/- 15.5 ng of Ang I/ml/h; P = 0.004) but did not affect baseline angiotensin-converting enzyme activity or aldosterone. HOE-140 tended to increase the PRA response to valsartan, and it attenuated the decrease in aldosterone following chronic valsartan (P = 0.03). Acute valsartan decreased mean arterial pressure 12.7 +/- 6.9% (from 100.2 +/- 8.4 to 87.5 +/- 9.8 mm Hg in hypertensives and from 82.4 +/- 8.6 to 70.3 +/- 8.4 mm Hg in normotensives). HOE-140 did not affect the blood pressure response to either acute (effect of valsartan, P < 0.001; effect of HOE-140, P = 0.98) or chronic (valsartan, P = 0.01; HOE-140, P = 0.84) valsartan. Plasma cGMP was increased significantly during chronic valsartan (P = 0.048) through a bradykinin receptor-independent mechanism (effect of HOE-140, P = 0.13). Both acute (P < 0.001) and chronic (P < 0.001) valsartan increased heart rate. HOE-140 augmented the heart rate response to chronic valsartan (P = 0.04). These data suggest that endogenous bradykinin does not contribute significantly to the blood pressure-lowering effect of valsartan through its B(2) receptor.
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19 MeSH Terms
COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia.
Woodward ND, Jayathilake K, Meltzer HY
(2007) Schizophr Res 90: 86-96
MeSH Terms: Adult, Antipsychotic Agents, Catechol O-Methyltransferase, Clozapine, Cognition Disorders, Cohort Studies, Female, Follow-Up Studies, Genotype, Heterozygote, Homozygote, Humans, Male, Memory, Short-Term, Methionine, Neuropsychological Tests, Polymorphism, Single Nucleotide, Problem Solving, Prospective Studies, Schizophrenia, Treatment Outcome, Valine
Show Abstract · Added February 15, 2016
Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs). Specifically, several studies have identified an association between working memory and executive functions, and COMT val108/158met genotype in schizophrenia; although there have been several negative findings that are likely related to small sample sizes and, possibly, medication status of patients at the time of testing. The association between COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine was investigated in a relatively large prospective sample of patients with schizophrenia, most of whom were unmedicated at baseline. Patients were genotyped for the COMT val108/158met SNP after completing a cognitive battery consisting of tests of attention, working memory, verbal learning and memory, executive function, and verbal fluency at baseline and after 6 weeks and 6 months of treatment with clozapine. Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and val/met heterozygous patients demonstrated significantly greater improvement than val homozygous patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype, cognition, and cognitive improvement with atypical APDs in schizophrenia.
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22 MeSH Terms
Random mutagenesis of Helicobacter pylori vacA to identify amino acids essential for vacuolating cytotoxic activity.
McClain MS, Czajkowsky DM, Torres VJ, Szabo G, Shao Z, Cover TL
(2006) Infect Immun 74: 6188-95
MeSH Terms: Amino Acid Substitution, Bacterial Proteins, Cytotoxins, Dimerization, Glycine, HeLa Cells, Helicobacter pylori, Humans, Hydrophobic and Hydrophilic Interactions, Mutagenesis, Serine, Vacuoles, Valine
Show Abstract · Added March 5, 2014
VacA is a secreted toxin that plays a role in Helicobacter pylori colonization of the stomach and may contribute to the pathogenesis of peptic ulcer disease and gastric cancer. In this study, we analyzed a library of plasmids expressing randomly mutated forms of recombinant VacA and identified 10 mutant VacA proteins that lacked vacuolating cytotoxic activity when added to HeLa cells. The mutations included six single amino acid substitutions within an amino-terminal hydrophobic region and four substitutions outside the amino-terminal hydrophobic region. All 10 mutations mapped within the p33 domain of VacA. By introducing mutations into the H. pylori chromosomal vacA gene, we showed that secreted mutant toxins containing V21L, S25L, G121R, or S246L mutations bound to cells and were internalized but had defects in vacuolating activity. In planar lipid bilayer and membrane depolarization assays, VacA proteins containing V21L and S25L mutations were defective in formation of anion-selective membrane channels, whereas proteins containing G121R or S246L mutations retained channel-forming capacity. These are the first point mutations outside the amino-terminal hydrophobic region that are known to abrogate vacuolating toxin activity. In addition, these are the first examples of mutant VacA proteins that have defects in vacuolating activity despite exhibiting channel activities similar to those of wild-type VacA.
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13 MeSH Terms