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At least 289 records · Page 16Linked to original sources
PubMed1990

Involvement of lactic acidosis in anoxia-induced perturbations of synaptosomal function.

L-Lactate (4-32 mM) added exogenously to resting or depolarised rat forebrain synaptosomes led to a significant decrease in intrasynaptosomal pH. Similarly depolarisation-induced increases in intrasynaptosomal calcium, calcium uptake, and acetylcholine release were all inhibited. These effects mimicked those previously observed in synaptosomes under anoxic conditions and suggest that lactate may be involved in limiting the damage due to calcium accumulation occurring during ischaemia. D-Lactate (added exogenously up to 32 mM) did not produce similar effects on these parameters even though the concentrations of intrasynaptosomal D-lactate reached levels comparable to those obtained with L-lactate (at 8-16 mM exogenous concentration). The results suggest that the mechanism of action of lactate on these parameters is stereospecific for the L-enantiomer. The effect of glucose availability on lactate production was assessed to explore the role of substrate availability on ischaemia/anoxic events. When exogenous glucose was increased (10-60 mM), there was no further increase in lactate production in normoxic synaptosomes, which suggests that glucose is not limiting under these conditions. When glucose was removed, as may occur in complete ischaemia, there was a significant decrease in lactate production after 60 min under anoxic or normoxic conditions. It would seem likely therefore that the mechanism underlying the changes observed in synaptosomes incubated under conditions reflecting complete ischaemia does not involve lactate.

Acidosis, Lactic↗
PubMed2001

Natural substitutions at highly conserved T1-domain residues perturb processing and functional expression of squid Kv1 channels.

Shaker-type K-channel alpha-subunits (SqKv1A, B, D) expressed in neurons of the squid stellate ganglion differ in the length of their N-termini and in the species of amino acid present at several points in the T1 domain, an intracellular region involved in the tetramerization process during channel assembly. Heterologous expression of wild-type SqKv1A, B, and D in Xenopus oocytes reveals large differences in the level of both functional channels (assayed by whole-oocyte voltage clamp) and total channel protein (assayed by immunoblotting). Functional expression is poorest with SqKv1A and by far the best with SqKv1D. Biophysical properties of the three SqKv1 channels are essentially identical (assayed by cell-attached patch clamp). Site-directed mutagenesis was used to determine whether the observed differences in expression level are impacted by two residues in the T1 domain at which SqKv1A and B (but not D) differ from the consensus sequences found in many other taxa. In SqKv1A, glycine is substituted for arginine in an otherwise universally conserved sequence (FFDR in the T1(B) subdomain). In SqKv1B, glycine replaces serine in a sequence that is conserved within the Kv1 subfamily (SGLR in the T1(A) subdomain). Restoration of the consensus amino acid at these positions largely accounts for the observed differences in expression level. Analysis of the glycosylation state of aberrant versus restored alpha-subunits suggests that the anomalous amino acids in SqKv1A and B exert their influence during early steps in channel processing and assembly which take place in the endoplasmic reticulum (ER).

Amino Acid Sequence↗
PubMed1993

Functional and metabolic perturbations in isolated pancreatic islets from the GK rat, a genetic model of noninsulin-dependent diabetes.

Spontaneously diabetic nonobese GK rats exhibit high basal plasma glucose and insulin levels and a poor insulin secretory response to glucose. We studied insulin biosynthesis, insulin release, and glucose metabolism in freshly isolated islets from GK rats and control Wistar rats. In GK rats, islet insulin content was decreased when expressed per islet but normal when related to DNA content. In the presence of a low concentration (2.8 mM) of glucose both (pro)insulin and total protein biosynthesis was doubled in islets from GK rats. As judged from the (pro)insulin/total protein synthesis ratio, (pro)insulin biosynthesis was normally stimulated by 16.7 mM glucose. In islets from diabetic rats both basal and glucose-stimulated insulin release were dramatically decreased. A reduced secretory response to 10 mM leucine or 10 mM leucine plus 10 mM glutamine and a lack of response to 10 mM monomethylsuccinate were observed. By contrast the insulinotropic capacity of nonnutrient secretagogues such as 62 microM gliclazide or the combination of 2 mM Ba2+ and 1.4 mM theophylline in the absence of extracellular Ca2+ remained normal. Glucose oxidation (estimated as the production of 14CO2 from D-[6-14C]glucose) was severely impaired, whereas no major alteration of glycolytic flux (as judged from the conversion of D-[5-3H]glucose to 3H2O) could be detected. Accordingly, the D-[6-14C]glucose oxidation/D-[5-3H]glucose use ratio was less markedly increased in response to a rise in glucose concentration in islets from GK rats than in islets from control rats. Thus, in islets from diabetic GK rats, glucose-induced insulin release but not insulin biosynthesis was impaired. This defect is associated with, and probably at least in part due to, a deficient oxidative metabolism of glucose in islet mitochondria.

Animals↗
PubMed2002

Regulation and perturbation of testicular functions by vitamin A.

In addition to playing a fundamental role in very diverse processes such as vision and the growth and differentiation of numerous types of cell, vitamin A (retinol) and its principal biologically active derivative, retinoic acid, are clearly involved in the regulation of testicular functions in rodents. An excess of vitamin A leads to testicular lesions and spermatogenetic disorders, and a deficiency induces early cessation of spermatogenesis and adversely affects testosterone secretion. Furthermore, mice mutant for retinoic acid alpha receptors and retinoid X beta receptors are sterile. Retinoids appear to exert an action on the three main testicular types of cell (Sertoli, germinal and Leydig cells), as they act on the signalling pathways and Sertoli cell metabolism, and modify numerous factors secreted in Sertoli cells. Retinoids also appear to be necessary for the proliferation and differentiation of A spermatogonia, and for spermiogenesis. In addition, vitamin A deficiency leads to atrophy of the accessory sex organs after decreased testosterone production. Recent studies have shown that retinoids already affect these three types of cell in fetuses. Curiously, the effects of retinoids on fetal and adult testis seem opposed.

Animals↗
PubMed1991

Enhancement of the cytotoxicity of mistletoe lectin-1 (ML-1) by high pH or perturbation in Golgi functions.

We have studied the cytotoxicity of Mistletoe lectin-1 (ML-1), a cytotoxic protein produced by Viscum album, in CHO and V79 cells and in mutant cell lines altered in Golgi functions or in endosomal acidification. In wild-type CHO cells, cytotoxicity of ML-1 was greatly enhanced by ammonium chloride or nigericin. A CHO mutant defective in endosomal acidification (DMPR-2), which is resistant to diphtheria toxin, modeccin and Pseudomonas aeruginosa exotoxin A and hypersensitive to ricin, showed increased sensitivity to ML-1. MonR-31 and MF-1 are monensin- and compactin-resistant mutants derived from CHO and V79 cell lines, respectively, and are presumably altered in Golgi functions. The cytotoxicity of ML-1 was found to be increased in both MonR-31 and MF-1 cells as compared with their parental cells. These results indicate that the effects of chemicals or mutations altering endosomal acidification and Golgi functions on the cytotoxicity of ML-1 are similar to those on ricin cytotoxicity. Our results suggest that the cytotoxicity of ML-1 is enhanced by an increase in endosomal pH, as well as by chemicals or mutations altering the structure/functions of the Golgi regions. Like ricin, the intoxication process of ML-1 may involve the Golgi regions.

Ammonium Chloride↗
PubMed1990

Perturbation of differentiated functions during viral infection in vivo. In vivo relationship of host genes and lymphocytic choriomeningitis virus to growth hormone deficiency.

Retarded growth and disordered glucose metabolism secondary to growth hormone (GH) deficiency are associated with persistent lymphocytic choriomeningitis virus (LCMV) infection of GH-producing cells in the anterior lobe of the pituitary gland. Infected C3H/ST mice, which are H-2k haplotype, become GH deficient, and LCMV replicates in most (more than 90%) of their GH-producing cells. In contrast, BALB/WEHI and SWR/J mice, which are H-2d and H-2q, respectively, do not develop this GH deficiency, and less than 20% of their GH-producing cells are infected by virus. Yet all three strains infected at birth with LCMV strain Armstrong (ARM) carry equivalent amounts of virus in their blood, brain, heart, kidney, liver, spleen, and thymus throughout life. Of five additional H-2k murine strains tested, C3H/HEJ and CBA/N mice develop this GH-like disorder, whereas neither AKR/J, B10/BR, nor BALB/KAE mice do, indicating that the H-2K haplotype does not control the GH susceptibility. Furthermore C3H/SW mice, which have the H-2b haplotype on the C3H background, develop the disease, again negating any correlation with H-2k but inferring that the C3H background is responsible. One half of the hybrid offspring produced by crossing the C3H/ST GH-deficient strain with BALB/WEHI-resistant mice develop the disease, but the trait is not sex linked. F1 hybrid backcrosses with the susceptible C3H/ST parental strain or resistant BALB/WEHI strain indicate the involvement of more than two genes. Hence the development of a GH deficiency by LCMV-infected C3H/ST mice is not linked to the MHC haplotype, is not sex linked, and is not due to a dominant gene. Multiple genes are involved and these are related to C3H background.

Animals↗
PubMed1986

Resolving pathways of functional coupling within protein assemblies by site-specific structural perturbation.

Site-specific structural modification is a powerful tool for studying functional mechanisms in proteins where the structures may be manipulated by direct chemical modification, by selection of naturally-occurring mutants, or by site-directed mutagenesis. Here, we present a general strategy for such studies, which we term "mapping by structure-function perturbation." A series of functional perturbations (i.e., deviations of functional behavior from that of the native protein) are mapped against the structural locations of the modified sites, obtained over a range of locations. The modifications are treated as arbitrary perturbations of structure at specific locations, in contrast to the conventional approach of trying to interpret their local stereochemistry. The map yields information on structural locations of functional events and pathways of coupling within protein assemblies. We have applied this approach to the ligand-linked subunit assembly of human hemoglobin, using both chemically-modified heme sites (CN-met), and amino acid residues altered by mutation and chemical modification.

Hemoglobins↗
PubMed2004

Resonance Raman spectra of uracil based on Kramers-Kronig relations using time-dependent density functional calculations and multireference perturbation theory.

The use of time-dependent density functional calculations for the optimization of excited-state structures and the subsequent calculation of resonance Raman intensities within the transform-theory framework is compared to calculations of Hartree-Fock/configuration interaction singles-type (CIS). The transform theory of resonance Raman scattering is based on Kramers-Kronig relations between polarizability tensor components and the optical absorption. Stationary points for the two lowest excited singlet states of uracil are optimized and characterized by means of numerical differentiation of analytical excited-state gradients. It is shown that the effect of electron correlation leads to substantial modifications of the relative intensities. Calculations of vibrational frequencies for ground and excited states are carried out, which show that the neglect of Duschinsky mixing and the assumption of equal wave numbers for ground and excited state are not in all cases good approximations. We also compare the transform-theory resonance Raman intensities with those obtained within a simple approximation from excited-state gradients at the ground-state equilibrium position, and find that they are in qualitative agreement in the case of CIS, but show some important differences in calculations based on density functional theory. Since the results from CIS calculations are in better agreement with experiment, we also present approximate resonance Raman spectra obtained using excited-state gradients from multireference perturbation theory calculations, which confirm the CIS gradients.

Journal Article↗
PubMed2006

Relativistic quasidegenerate perturbation theory with four-component general multiconfiguration reference functions.

Relativistic quasidegenerate perturbation theory (QDPT) using general multiconfiguration (GMC) reference functions is developed and implemented. It is the relativistic counterpart of the nonrelativistic QDPT with GMC reference and thus retains all the advantages of the nonrelativistic GMC reference QDPT, such as applicability to any configuration space and small computational cost compared to the complete configuration-space case. The method is applied to the potential-energy curves of the ground states of I(2) and Sb(2) molecules, the excitation energies of CH(3)I, and the energies of the lowest terms of C, Si, and Ge atoms, and is shown to provide a balanced description of potential-energy curves and accurate transition energies for systems containing heavy elements and to provide much better results compared to the reference function (i.e., active space configuration interaction) level.

Journal Article↗