Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the 45 years since the first description of choline acetyltransferase (ChAT; EC 2.3.1.6.), significant progress has been made in characterizing the molecular properties of this important neurotransmitter synthetic enzyme. We are now on the verge of understanding its genetic regulation and biological function(s). The Drosophila cDNA has been cloned, sequenced, and expressed in both a eucaryotic and a procaryotic system. The levels of ChAT specific mRNA have been determined during Drosophila development. Monoclonal and polyclonal antibodies have been produced to the enzyme from a variety of sources and used for biochemical and immunocytochemical studies. Two well characterized genetic systems have identified the ChAT gene and described a series of useful alleles. As a nervous system specific protein expressed only in the subset of neurons using acetylcholine as a neurotransmitter, ChAT is a good model for uncovering the processes and factors responsible for regulating genes involved in neurotransmitter phenotype selection and maintenance. Recent studies have described the purification of a cholinergic factor from muscle conditioned medium and indicated the potential importance of nerve growth factor (NGF) for regulating ChAT expression in the central nervous system. These factors, or ones remaining to be discovered, may be involved in the etiology or disease process of neurodegenerative nervous system disorders such as Alzheimer's disease.
Mol Neurobiol 1987
PMID:Molecular biology and neurobiology of choline acetyltransferase. 307 61

In vitro neural systems can be predictive for CNS neurotoxicity, except where xenobiotics primarily affect the blood-brain barrier. The wide range of systems now used in neurobiological studies is available for mechanistic neurotoxicological investigations although the choice of system is generally arbitrary. A more rational approach may now be justified. There are many culture systems available including neural cell lines, organotypic explant or reaggregation cultures, and primary monolayer cultures of individual neural cell types: neurons, astrocytes, and oligodendrocytes. Of these models much success has recently been achieved using the organotypic explant culture type. Similarly in our laboratories, using rat whole-brain reaggregate cultures, we have demonstrated good in vitro/in vivo correlations for the cholinergic neurotoxicant ethylcholine mustard aziridinium (ECMA) where specific cholinergic lesions are produced using low concentrations of ECMA (12.5 microM). Higher concentrations (25-50 microM) were more cytotoxic, as shown, for example, by nonspecific effects on cerebellar glutamatergic granule neurons. Treatment of reaggregates lesioned with the cholinotoxin with a neurotrophic factor, nerve growth factor (NGF), did not reverse the lesion but treatment of control cells with NGF (50 ng/ml) elevated both choline acetyltransferase (ChAT) activity and muscarinic receptor binding. The "lesioned" reaggregate culture system may thus be of future value in evaluating potential therapeutic agents that could reverse such lesions in the CNS. By supplementing the information gained in the reaggregate system with tests using primary monolayer cultures of neurons or astrocytes we can propose a stepwise screening system for potential neurotoxicants in vitro. In its simplest form this is (1) screen initially using tumor-derived neural cell line, (2) test selected compounds in whole-brain reaggregates, and (3) supplement information with primary monolayer cultures of individual neural cell types.
Mol Toxicol
PMID:Brain reaggregate cultures in neurotoxicological investigations: adaptational and neuroregenerative processes following lesions. 350 99

The hypothesis that peripheral, skeletal muscle tissue contains a trophic factor supporting central neurons has recently been investigated in vitro by supplementing the culture medium of spinal cord neurons with muscle extracts and fractions of extract. We extended these studies asking whether or not a trophic factor is present in peripheral nerves, the connecting link between muscle and central neurons via which factors may be translocated from muscle to neurons by the retrograde transport system. Lumbar, 8-day-old chick spinal cords were dissociated into single cells and then cultured in the presence of peripheral nerve extract. Cytosine arabinoside was added to inhibit proliferation of nonneuronal cells. In the presence of nerve extract, spinal cord neurons survived for more than a month, extended numerous neurites, and showed activity of choline acetyltransferase. In the absence of extract, neurons attached and survived for a few days but then died subsequently in less than 10 days. Neurite outgrowth did not occur in the absence of extract. Withdrawal of extract from the medium of established neuronal cultures caused progressive loss of both cells and neurites. Other tissues also contained neuron supporting activity but less than that found in nerve extract. These studies indicate that peripheral nerves contain relatively high levels of spinal cord neuron-directed trophic activity, suggesting translocation of neurotrophic factor from muscle to central target neurons. The neurotrophic factor has long-term (weeks) effects, whereas short-term (days) survival is factor independent.
Cell Mol Neurobiol 1984 Mar
PMID:Peripheral nerve extract promotes long-term survival and neurite outgrowth in cultured spinal cord neurons. 674 70

To elucidate the sequence of molecular events leading to nerve terminal differentiation, we have examined the regulation of expression of presynaptic protein genes during synapse formation in vivo. In the chick ciliary ganglion (CG), synaptophysin IIa and synaptophysin IIb mRNAs showed threefold increases relative to neurofilament-M mRNA during the time of target contact [Embryonic Day 7 (E7)-E9]. Expression of synaptotagmin I mRNA also increased severalfold over this time interval. Thus, mRNAs for three synaptic vesicle proteins are upregulated coordinately during synaptogenesis. In contrast, the major increase in choline acetyltransferase (ChAT) mRNA (four- to fivefold) occurred between E15 and E20, coincident with the maturation of synapses in the CG. Coincident with ChAT upregulation, there is a switch in the relative abundance of mRNAs encoding vesicle protein isoforms. In particular, mRNAs encoding synaptophysin IIb and synaptotagmin II (which is undetectable at E9) become predominant. Therefore, although synaptic vesicle protein mRNAs are upregulated in a first phase of differentiation at the time of synapse formation, a temporally distinct phase of presynaptic protein gene regulation, associated with the specific maturation of synapses, is also apparent.
Mol Cell Neurosci 1995 Jun
PMID:Patterns of presynaptic gene expression define two stages of synaptic differentiation. 749 30

The expression of mRNA for the calmodulin-dependent form of brain nitric oxide synthase (NOS) was examined in cholinergic cells of the rat brain using a method combining in situ hybridization histochemistry with immunocytochemistry for choline acetyltransferase (ChAT) in the same brain sections. We constructed a riboprobe specific for brain NOS by subcloning a 493 bp fragment of the coding region which displayed low homology to other forms of NOS. The general distribution of NOS mRNA was in excellent agreement with previous studies using the full-length probe or NADPH diaphorase histochemistry. NOS mRNA was observed in many brain structures and relative levels were quantitated using grain counting procedures in a number of cholinergic and non-cholinergic neuronal groups throughout the brain. In the forebrain, ChAT-immunoreactive cells or cell groups were observed in medial septum (MS), vertical limbs of diagonal band (DBV) and horizontal limbs of diagonal band (DBH), nucleus basalis magnocellularis (NBM), substantia innominata (SI), and striatum (ST). In the brainstem, the cholinergic groups studied included those located in the pedunculopontine tegmental nucleus (PPTN), the laterodorsal tegmental nucleus (LDTN), the nucleus parabigeminalis and several motor nuclei. For NOS mRNA quantitation, silver grains overlying ChAT-stained neuronal profiles in sections on emulsion-dipped slides were counted digitally. In the LDTN and PPTN, virtually all the ChAT-positive cells expressed NOS mRNA at high levels. In MS, DBV and SI, about 30-50% of the ChAT-positive cells expressed NOS mRNA at low-to-moderate levels. Less than 20% of ChAT-positive neurons in the other cholinergic populations studied expressed NOS mRNA; the NBM was one of these low-expressing populations. Many scattered non-cholinergic cells expressing NOS mRNA were found in the striatum and cerebral cortex. In other non-cholinergic regions, high NOS mRNA expression was observed in the islands of Calleja, thalamic and hypothalamic nuclei, several amygdaloid nuclei, regions related to the optic tract, the interpeduncular nucleus, and the supramammillary nucleus. The heterogeneous distribution of NOS mRNA implies complex roles for nitric oxide neurotransmission in brain function, including for the cholinergic phenotype. Additionally, given the postulated involvement of nitric oxide in neurodegeneration, the widely varying levels of expression of NOS within identified central cholinergic neurons may relate to differential vulnerability of this phenotype in disease or aging.
Brain Res Mol Brain Res 1994 Apr
PMID:Nitric oxide synthase gene expression in cholinergic neurons in the rat brain examined by combined immunocytochemistry and in situ hybridization histochemistry. 751 28

We have previously reported that cholinergic neuron-specific expression of the human choline acetyltransferase gene is mediated by two co-operative silencers. We have now localized the proximal silencer to the region from nucleotide -2195 to -2409, which contains two distinct E boxes (CACCTG and CATGTG). Deletion or mutation of either of these E boxes results in a loss of silencer activity. There are specific nuclear proteins in adrenergic cells which bind to each of the two E boxes. However, nuclear proteins from cholinergic cells only bind the 5' E box not the 3' E box. It is this interaction which appears to be the cause of the inactivity of this silencer in these cells.
Brain Res Mol Brain Res 1995 May
PMID:A cell type-specific silencer in the human choline acetyltransferase gene requiring two distinct and interactive E boxes. 760 31

Alzheimer's disease and cognitive impairment in rats has been associated with an increase in the percentage of amyloid precursor protein (APP) containing the KPI domain. It has recently been reported that retinoic acid (RA) is capable of increasing the levels and altering the splicing ratio of APP in cultured SH-SY5Y cells. The effects of peripherally administered RA (64 or 640 micrograms/kg; i.p.; q.d.) on the abundance of APP, the ratio of the three major isoforms, and the relative abundance of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were determined by rtPCR in the hippocampus of aged rats. Corresponding changes in choline acetyltransferase (ChAT) activity were also measured. Vehicle (DMSO) treated rats exhibited a 2 x (P < 0.01) increase in total APP and an 8 x (P < 0.001) decrease in the cyclophilin transcript. In addition, DMSO increased the percentage of APP 695 from 89% in saline treated rats to 94%. Treatment of RA in DMSO decreased the accumulation of total APP relative to cyclophilin at both the low (6.4 x; P < 0.01) and high (8 x; P < 0.05) dosages when compared to DMSO treated rats. Furthermore, the level of APP-695 decreased to 82% with low dosage of RA and 75% at high dosage of the total APP transcripts. No significant change in either NGF, NT-3, or BDNF transcripts were observed following low or high dosage RA administration relative to cyclophilin RNA nor was a change in ChAT activity detected at either of the dosages tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Res Mol Brain Res 1993 May
PMID:Altered levels and splicing of the amyloid precursor protein in the adult rat hippocampus after treatment with DMSO or retinoic acid. 768 85

Haloperidol, a dopamine receptor antagonist clinically used as an antipsychotic drug, induces long-term deleterious effects in offspring development when administered prenatally. However, the basis for this overall response to the drug remains unknown. Here we describe that prenatal administration of haloperidol in rats induces a drastic and selective reduction in the expression of plasticity-related genes in neonate forebrain, but not in mesencephalon. GABAergic and enkephalinergic markers such as glutamic acid decarboxylase activity and mRNA, and preproenkephalin mRNA were also diminished in forebrain. However, the expression of other genes such as epidermal growth factor-receptor, glial fibrillary acidic protein, and several proto-oncogenes (src, fos and myc), and a cholinergic marker such as choline acetyltransferase activity were unaltered. In addition, haloperidol promoted a significant decrease in mitotic cell number and cellular density in the striatum, one of the forebrain regions with the highest dopamine receptor density. These findings suggest that prenatal dopamine receptor occupancy may be a critical factor in controlling the development of forebrain target cells through mechanisms involving changes in the expression of plasticity-related genes.
Brain Res Mol Brain Res 1994 Oct
PMID:Prenatal haloperidol induces a selective reduction in the expression of plasticity-related genes in neonate rat forebrain. 785 69

Expression of the acetylcholine biosynthetic enzyme choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (VAChT), and the high-affinity plasma membrane choline transporter uniquely defines the cholinergic phenotype in the mammalian central (CNS) and peripheral (PNS) nervous systems. The distribution of cells expressing the messenger RNA encoding the recently cloned VAChT in the rat CNS and PNS is described here. The pattern of expression of VAChT mRNA is consistent with anatomical, pharmacological, and histochemical information on the distribution of functional cholinergic neurons in the brain and peripheral tissues of the rat. VAChT mRNA-containing cells are present in brain areas, including neocortex and hypothalamus, in which the existence of cholinergic neurons has been the subject of debate. The demonstration that VAChT is a completely adequate marker for cholinergic neurons should allow the systematic delineation of cholinergic synapses in the rat nervous system when antibodies directed to this protein are available.
J Mol Neurosci 1994
PMID:Distribution of the vesicular acetylcholine transporter (VAChT) in the central and peripheral nervous systems of the rat. 785 78

Trimethyltin (TMT) destroys specific subfields of the hippocampus in the rat. TMT also increases choline acetyltransferase (ChAT) activity in CA1 of Ammon's horn and the outer molecular layer of the dentate gyrus. This observation suggests that axonal sprouting occurs in the cholinergic septohippocampal system in response to TMT. However, neither does-response nor time course data are available for the effects of TMT on this enzyme. The effects of three dose levels of TMT on ChAT activity in CA1 and the dentate gyrus were determined in Experiment 1 and ChAT activity in these two areas was measured at six time points following exposure to TMT in Experiment 2. Only the highest dose of TMT (6 mg/kg) significantly increased ChAT activity. ChAT activity in the dentate gyrus increased significantly by 3 d after administration and continued to increase until 21 d after exposure. A significant increase was not observed in CA1 until 7 d after exposure to TMT. Asymptotic levels were still reached at d 21. These results indicate a steep dose-response curve for TMT-induced changes in ChAT activity in the hippocampal formation and that this marker of cholinergic activity is more sensitive to perturbation by TMT in the dentate gyrus than Ammon's horn.
Mol Chem Neuropathol 1994 Sep
PMID:Effects of trimethyltin (TMT) on choline acetyltransferase activity in the rat hippocampus. Influence of dose and time following exposure. 789 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>