Homozygosity at the dopamine D3 receptor locus is not associated with schizophrenia.
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Alleles↗
Biomedical subjects
J Mallet
Publications and source records attributed to J Mallet.
Ticlopidine and fatal aplastic anemia in an elderly woman.
OBJECTIVE: To report a case of aplastic anemia that developed during ticlopidine treatment. CASE SUMMARY: An 84-year-old woman was started on ticlopidine for secondary stroke prevention. Within six weeks of initiating ticlopidine therapy she developed aplastic anemia. She was hospitalized and received empiric antibiotics, antifungal agents, blood transfusions, platelets, and granulocyte colony-stimulating factor. The patient died on day 76 after beginning ticlopidine. DISCUSSION: Hematologic effects such as neutropenia, thrombocytopenia, agranulocytosis, thrombotic thrombocytopenic purpura, and pancytopenia have been described with the use of ticlopidine. Previous case reports have associated ticlopidine with the development of aplastic anemia. CONCLUSIONS: Ticlopidine can produce fatal hematologic adverse effects, and its use should be reserved as second-line therapy.
Aged↗
Adenovirus insertion encoding the Lac Z gene in human nervous cells in primary dissociated cultures.
Primary dissociated cultures of human fetal central nervous system cells were prepared and inoculated at different days in vitro with adenovirus that contained a reporter gene encoding beta-galactosidase. At various time intervals, the cultures were processed for characterization with X-gal histochemistry and additional immunostaining with neurofilament (NF), GABA and glial fibrillary acidic protein (GFA-P). We observed that NF (+) and GABA (+) neuronal as well as GFA-P (+) glial cells could express beta-galactosidase activity after inoculation. The labeling was detected up to 3 months after virus treatment. In addition, neurons cultivated for three months were found to be still permissive for virus infection. We can conclude that adenovirus may be considered as a potential vector to transfer genes to nerve cells.
Adenoviruses, Human↗
Adenovirus mediated gene transfer to the central nervous system.
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Adenoviridae↗
Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2.
Mitogen-activated protein-kinase (MAP) kinase-activated protein kinases 1 and 2 (MAPKAP kinase-1, MAPKAP kinase-2), were found to phosphorylate bacterially expressed human tyrosine hydroxylase in vitro at comparable rates to other proteins thought to be physiological substrates of these protein kinases. The phosphorylation of all four alternatively spliced forms of human tyrosine hydroxylase by MAPKAP kinases-1 and -2 reached plateau values at 1 mol/mol subunit and 2 mol/mol subunit, respectively; the sites of phosphorylation were identified as Ser40 (MAPKAP kinase-1) and Ser19 and Ser40 (MAPKAP kinase-2). In contrast to calmodulin-dependent protein kinase-II, which phosphorylates Ser19 faster than Ser40, MAPKAP kinase-2 phosphorylated Ser40 about twice as fast as Ser19. The maximal activation of tyrosine hydroxylase by MAPKAP kinase-1 or-2 was about 3-fold, and activation by MAPKAP kinases-1 and -2 or calmodulin-dependent protein kinase-II correlated with the extent of phosphorylation of Ser40. The four alternatively spliced forms of human tyrosine hydroxylase were phosphorylated at Ser31 by MAP kinase, but at markedly different rates (3 = 4 > 1 >> 2). Forms 3 and 4 were phosphorylated rapidly and stoichiometrically by MAP kinase doubling the activity, while phosphorylation of form 1 by MAP kinase to 0.4 mol/mol subunit increased activity by 40%. The effect on activity of phosphorylating both Ser31 and Ser40 was not additive. The possible roles of MAPKAP kinase-1, MAPKAP kinase-2 and MAP kinase in the regulation of tyrosine hydroxylase in vivo are discussed.
Alternative Splicing↗
Characterization of a presynaptic glutamate receptor.
Glutamate receptors mediate excitatory neurotransmission in the brain and are important in the formation of memory and in some neurodegenerative disorders. A complementary DNA clone that encoded a 33-kilodalton protein (GR33) was obtained by screening a library with an antibody generated against glutamate binding proteins. The sequence of GR33 is identical to that of the recently reported presynaptic protein syntaxin. When GR33 was expressed in Xenopus oocytes, it formed glutamate-activated ion channels that are pharmacologically similar to those of N-methyl-D-aspartate receptors but with different electrophysiological properties. Mutation of the leucine 278 residue in the single putative transmembrane segment of GR33 affects the properties of the channel. Thus, in vivo GR33 may be a presynaptic glutamate receptor.
Animals↗
Transsynaptic expression of a presynaptic glutamate receptor during hippocampal long-term potentiation.
Repetitive activation of excitatory synapses in the hippocampus produces a persistent enhancement of synaptic efficiency known as long-term potentiation (LTP). In anesthetized and in freely moving rats, the induction of LTP in the perforant path led to a transient increase in the amount of messenger RNA (mRNA) coding for a presynaptic glutamate receptor (GR33) in dentate granule cells. The amount of GR33 mRNA was increased for at least 5 hours after the induction of LTP but was indistinguishable from control values 1 day after induction. The N-methyl-D-aspartate receptor antagonist 2-aminophosphonovalerate prevented the induction of both LTP and the increase in GR33 mRNA. The amount of GR33 protein was increased in the mossy fiber terminal zone of dentate granule cells 5 hours after the induction of LTP. These results suggest that the induction of LTP in synapses at one stage in a neural network may lead to modification in synaptic function at the next stage in the network.
2-Amino-5-phosphonovalerate↗
Retinoic acid induces cholinergic differentiation of cultured newborn rat sympathetic neurons.
Many studies provide evidence that retinoic acid (RA), an endogenous derivative of vitamin A, plays a role in the development of the nervous system. We now report that RA controls the neurotransmitter phenotype of post-mitotic rat sympathetic neurons in cell culture. RA added to the culture medium increased the specific activity of choline acetyltransferase (ChAT) and the level of acetylcholine (ACh). Concomitantly, RA reduced the specific activities of two catecholamine synthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) and the level of norepinephrine (NE). After a 2 week treatment with 5 microM RA, ChAT was increased by 5-10 fold, whereas TH and DBH were decreased by 10-15 fold and 2-3 fold, respectively, as compared to sympathetic neurons grown in the absence of RA. The modulation of the activity of the three enzymes was dose-dependent and followed a similar time course. The decrease of TH expression was demonstrated to be due to a decreased number of TH molecules.
Acetylcholine↗
An adenovirus vector for gene transfer into neurons and glia in the brain.
The efficient introduction of genetic material into quiescent nerve cells is important in the study of brain function and for gene therapy of neurological disorders. A replication-deficient adenoviral vector that contained a reporter gene encoding beta-galactosidase infected rat nerve cells in vitro and in vivo. beta-Galactosidase was expressed in almost all sympathetic neurons and astrocytes in culture. After stereotactic inoculations into the rat hippocampus and the substantia nigra, beta-galactosidase activity was detected for 2 months. Infected cells were identified as microglial cells, astrocytes, or neurons with anatomical, morphological, and immunohistochemical criteria. No obvious cytopathic effect was observed.
Adenoviridae↗
Bioamine receptors: evolutionary and functional variations of a structural leitmotiv.
Bioamines act as neurohormonal messengers through their binding to receptors which belong to the largest membrane protein family known so far: the seven spanning membrane receptors. This class of receptors transmits the effect of agonist binding to intracellular effectors by interacting with an intermediary G-protein. The diversity of receptor subtypes inside the protein family, observed in many animal species, is the result of a long evolutionary process. The tendency to protein diversification depends upon gene duplications and upon the continuous accumulation of mutations. The maintenance of vital functions in organisms, however, strictly requires enough structural conservation to ensure the functionality of the corresponding proteins. Both forces cooperate to ensure the adaptation of organisms to a changing environment. We have reviewed here the main conformational and functional constraints exerted on the structure of the bioamine receptors. They are mainly the transmembrane conformation of the receptors, their ability to bind ligands, to interact with G-proteins and to desensitize. The molecular basis of the biochemical and pharmacological differences used to classify the members of the receptor family have also been examined. Interestingly, this classification is very close to that obtained by the molecular phylogeny methods, used to elucidate the evolutionary relationships between bioamine receptors. However, this latter classification allows to accurately distinguish between different receptor subtypes (paralogous genes) and species homologous (orthologous genes). In addition, the calculation of phylogenetical distances reveals two main periods of diversification: the first one occurred before the separation of arthropods from vertebrates, in the Precambrian, and corresponds to the appearance of the main subtypes of the bioamine receptors. The second one, which occurred about 400 million years ago, might accompany the cephalization of the CNS in vertebrates.
Animals↗
Organochlorine pesticide and PCB congener content of French human milk.
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Eating↗
Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism.
We tested for an association between autism and genes coding for enzymes involved in monoaminergic metabolism and for a linked marker, c-Harvey-Ras-1 (HRAS 1), using restriction fragment length polymorphisms. We did not find evidence of an association between autism and genes coding for tyrosine hydroxylase, dopamine-beta-hydroxylase (DBH), and tryptophan hydroxylase. However, we report a positive association between autism and the locus containing the gene for HRAS-1.
Adolescent↗
Retroviral-mediated gene transfer of the porcine choline acetyltransferase: a model to study the synthesis and secretion of acetylcholine in mammalian cells.
We have constructed a recombinant retrovirus that expresses choline acetyltransferase (ChAT) by placing the porcine enzyme cDNA under the control of the 5' long terminal repeat of the retroviral vector pMMuLV. Using retrovirus-mediated gene transfer, we have expressed ChAT in astroglial (STR-SVLT) and neuroendocrine (RIN) cell lines. Both genetically modified cell types synthesize acetylcholine (ACh). ACh is also present in the culture medium at a low concentration relative to that found in the modified cells. This result suggests that the synthesized ACh is retained within the cells and released by these two cell types. Release of ACh is not increased in the presence of the calcium ionophore A23187 or by depolarizing concentrations of potassium in either STR-SVLT or in RIN cells. The implications of these studies for understanding ACh release mechanisms are discussed.
Acetylcholine↗
Tyrosine hydroxylase regulation in neurotransmission and neuroplasticity.
The modulation of neurotransmitter synthesis is a fundamental mechanism influencing neurotransmission and neuronal plasticity during development. The regulation of the tyrosine hydroxylase (TH) has been used to elucidate specific adaptative responses in neurons. Trans-synaptic impulse activity elicits sort- and long-term changes in the activity of TH. Acute regulation involves the activation of preexisting TH molecules via phosphorylation and possibly through alternative splicing events in humans, whereas long-term regulation results from an increased synthesis of the enzyme due in part to the transcriptional stimulation of the TH gene. The long-term increase of TH activity was addressed using the drug reserpine known to modify the secretion of neurotransmitters and the tetradecanoyl phorbol acetate (TPA). Inductions of TH expression by reserpine in vivo as well as by TPA in vitro seem to be mediated by an AP-1 complex acting on a TPA responsive element (TRE) of the rat TH promoter indicating that the TRE-TH site plays a critical role in trans-synaptic induction. Our results also demonstrate a degree of adaption by sympathetic neurons to their environment by conversion from adrenergic to cholinergic phenotype.
Cells, Cultured↗
Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human fetal brain.
The expression of the FMR-1 gene, which is implicated in fragile-X syndrome was investigated in human fetuses by in situ hybridization. In 8 and 9 week-old fetuses, FMR-1 mRNAs are expressed in proliferating and migrating cells of the nervous system, in the retina, and in several non-nervous tissues. In the brain of 25 week-old fetuses, FMR-1 mRNAs are produced in all nearly differenciated structures, with the highest level in cholinergic neurons of the nucleus basalis magnocellularis and in pyramidal neurons of hippocampus. The early transcription of FMR-1 gene and the distribution of FMR-1 mRNAs in human fetuses suggest that alterations of FMR-1 gene expression may contribute to the pathogenesis of fragile-X syndrome and especially the mental retardation.
Animals↗
No mutation in codon 713 of the amyloid precursor gene in schizophrenic patients.
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Amyloid beta-Protein Precursor↗
Antibodies to the human gamma 2 subunit of the gamma-aminobutyric acidA/benzodiazepine receptor.
A gamma-aminobutyric acidA (GABAA) receptor (GABAAR) gamma 2 subunit (short form) was cloned from an adult human cerebral cortex cDNA library in bacteriophage lambda gt11. The 261-bp intracellular loop (IL) located between M3 and M4 was amplified using the polymerase chain reaction and inserted into the expression vectors lambda gt11 and pGEX-3X. Both beta-galactosidase (LacZ) and glutathione-S-transferase (GST) fusion proteins containing the gamma 2IL were purified, and a rabbit antibody to the LacZ-gamma 2IL was made. The antibody reacted with the gamma 2IL of both LacZ and GST fusion proteins and immunoprecipitated the GABAAR/benzodiazepine receptor (GABAAR/BZDR) from bovine and rat brain. The antibody reacted in affinity-purified GABAAR/BZDR immunoblots with a wide peptide band of 44,000-49,000 M(r). Immunoprecipitation studies with the anti-gamma 2IL antibody suggest that in the cerebral cortex, 87% of the GABAARs with high affinity for benzodiazepines and 70% of the GABAARs with high affinity for muscimol contain at least a gamma subunit, probably a gamma 2. These results indicate that there are [3H]muscimol binding GABAARs that do not bind [3H]flunitrazepam with high affinity. Immunoprecipitations with this and other anti-GABAAR/BZDR antibodies indicate that the most abundant combination of GABAAR subunits in the cerebral cortex involves alpha 1, gamma 2 (or other gamma), and beta 2 and/or beta 3 subunits. These subunits coexist in > 60% of the GABAAR/BZDRs in the cerebral cortex. The results also show that a considerable proportion (20-25%) of the cerebellar GABAAR/BZDRs is clonazepam insensitive. At least 74% of these cerebellar receptors, which likely contain alpha 6, also contain gamma 2 (or other gamma) subunit(s). The alpha 1 and beta 2 or beta 3 subunits are also frequently associated with gamma 2 (or other gamma) and alpha 6 in these cerebellar receptors.
Antibodies↗
Analysis of the human dopamine beta-hydroxylase promoter: transcriptional induction by cyclic AMP.
We have analyzed some functional aspects of the promoter of the human dopamine beta-hydroxylase (DBH) gene. A fragment of 1,247 bp directly 5' to the transcriptional start was progressively shortened, placed in front of a reporter gene, and tested in a human neuroblastoma cell line expressing DBH (SK-N-SH-TFM) and in a monkey kidney cell line (CV-1). A remarkably short region (267 bp), directly upstream from the transcription start, was sufficient to confer activity and tissue-specific expression. Furthermore, the expression of the DBH gene was shown to be inducible by cyclic AMP in SK-N-SH-TFM cells. This effect was demonstrated to occur at the transcriptional level, as shown by run-on assays, and was due to the presence of a near-consensus cyclic AMP-responsive element located in the untranscribed 5' regulatory region of the gene.
Animals↗