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PubMed1977

Effects of acetylcholine mustard aziridinium ion and its choline analogue on choline transport into synaptosomes.

A compound thought to be choline mustard aziridimium ion was found previously in our laboratory to inhibit choline transport into human erythrocytes. Experiments with synaptosomes prepared from brain of rat now show that the aziridinium ion of choline mustard hydrochloride inhibited high- and low-affinity choline transport, with the inhibitory effect being about 10 times less than that of hemicholinium-3. Acetylcholine mustard aziridinium ion also inhibited the transport of choline, but it was less potent than its choline analogue. Studies with choline mustard aziridinium ion may yield important information about the transport of substances into the presynaptic nerve terminal.

Acetylcholine↗

PubMed2004

Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency.

Choline acetyltransferase (ChAT), the enzyme that synthesizes the neurotransmitter acetylcholine (ACh), is thought to be present in kinetic excess in cholinergic neurons. The rate-limiting factor in ACh production is the provision of choline to ChAT. Cholinergic neurons are relatively unique in their expression of the choline transporter 1 (CHT1), which exhibits high-affinity for choline and catalyzes its uptake from the extracellular space to the neuron. Multiple lines of evidence indicate that the activity of CHT1 is a key determinant of choline supply for ACh synthesis. We examined the interaction of ChAT and ChT activity using mice heterozygous for a null mutation in the Chat gene (Chat+/-). In these mice, brain ChAT activity was reduced by 40-50% relative to the wild type, but brain ACh levels as well as ACh content and depolarization-evoked ACh release in hippocampal slices were normal. However, the amount of choline taken up by CHT1 and ACh synthesized de novo from choline transported by CHT1 in hippocampal slices, as well as levels of CHT1 mRNA in the septum and CHT1 protein in several regions of the CNS, were 50-100% higher in Chat+/- than in Chat+/+ mice. Thus, haploinsufficiency of ChAT leads to an increased expression of CHT1. Increased ChT activity may compensate for the reduced ChAT activity in Chat+/- mice, contributing to the maintenance of apparently normal cholinergic function as reflected by normal performance of these mice in several behavioral assays.

Acetylcholine↗

PubMed1982

Induction of choline kinase by polycyclic aromatic hydrocarbons in rat liver. I. A comparison of choline kinases from normal and 3-methylcholanthrene-induced rat liver cytosol.

Choline kinase in rat liver has been shown to be induced up to 2-fold by the administration of polycyclic aromatic hydrocarbon carcinogens such as 3-methylcholanthrene and 3,4-benzo[a]pyrene (Ishidate, K., Tsuruoka, M. and Nakazawa, Y., (1980) Biochem. Biophys. Res. Commun. 96, 946-952). In order to characterize the nature of choline kinase induction by these carcinogens, the 3-methylcholanthrene-induced form as well as the normal form of choline kinase were partially purified from rat liver cytosol through acid treatment, (NH4)2SO4 precipitation and DEAE-cellulose column chromatography with linear KCl-gradient elution, and the catalytic properties were compared between the two preparations. Both enzyme activities were purified about 17-fold with a yield of 50% through the purification steps and there appeared no detectable difference in the elution pattern from either DEAE-cellulose column or Sephadex G-200 gel filtration. On the other hand, some differences were observed in catalytic properties between the two enzyme preparations; (1) the induced form showed a higher apparent Km value for choline (0.19 mM) when compared to the normal form (0.11 mM) and (2) the addition of polyamines caused a considerable increase in the maximum reaction velocity for the normal form whereas no remarkable change for the induced form, when the activities were plotted as a function of choline concentration. The overall results suggest that the 3-methylcholanthrene-induced form of choline kinase in rat liver could be different from the normal form, or that there exist several isoenzymes of choline kinase in rat liver, and one or some of them are inducible by the administration of polycyclic aromatic hydrocarbons.

Adenosine Triphosphate↗

PubMed1984

Regulation of phosphatidylcholine metabolism in mammalian cells. Isolation and characterization of a Chinese hamster ovary cell pleiotropic mutant defective in both choline kinase and choline-exchange reaction activities.

By means of an in situ autoradiographic assay for the base-exchange reaction of phospholipids with L-serine in Chinese hamster ovary cell colonies immobilized on filter paper ( Esko , J.D. and Raetz , C.R.H. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 1190-1193), a mutant (designated 89.1) was isolated in which the specific activity of the serine-exchange enzyme was about 2-fold less than in the parent. Unexpectedly, it was demonstrated that in extracts of the mutant the specific activities of both ATP:choline phosphotransferase (choline kinase) (EC 2.7.1.32) and the enzyme that catalyzes the base-exchange of phospholipids with choline (choline-exchange enzyme) were strikingly reduced (3- to 4-fold and 10- to 15-fold, respectively), while the specific activities of other enzymes of phosphatidylcholine synthesis were normal. Several lines of evidence presented here suggested that the partial defect of serine-exchange activity in this mutant was due to a decrease of acceptor phospholipid(s) for the reaction. The growth rates and phospholipid compositions of the mutant and parent were quite similar. However, mutant 89.1 exhibited a significant defect in its ability in vivo to synthesize phosphatidylcholine. The fact that the mutant was also defective in phosphorylcholine biosynthesis in vivo, together with the finding of an enzymatic lesion of the mutant in choline kinse in vitro as described above, clearly demonstrated that with respect to the reduced phosphatidylcholine biosynthesis the primary defect was at the level of choline kinase. In addition to the decreased synthetic rate of phosphatidylcholine, the turnover rate of phosphatidylcholine was also reduced approximately 2-fold in this mutant. These decreased rates of both synthesis and degradation of phosphatidylcholine probably account for the identical phosphatidylcholine contents between the mutant and parent. As a conclusion, it may be given that strain 89.1 is a pleiotropic mutant which possesses several alterations in phosphatidylcholine metabolism, and such mammalian mutants have not been isolated previously.

Animals↗

PubMed1992

Effects of septal and/or raphe cell suspension grafts on hippocampal choline acetyltransferase activity, high affinity synaptosomal uptake of choline and serotonin, and behavior in rats with extensive septohippocampal lesions.

At 31 days of age, Long-Evans female rats sustained aspirative lesions of the septohippocampal pathways and, 14 days later, received intrahippocampal suspension grafts prepared from the region including the medial septum and the diagonal band of Broca (Group S, n = 11), from the region including the mesencephalic raphe (Group R, n = 11) or from both regions together (Group S+R, n = 11). Sham-operated (Group Sham, n = 9) and lesion-only (Group Les, n = 11) rats served as non-grafted controls. Seven Sham, 7 Les and 8 rats from each transplant group were tested for home cage activity (6 months after grafting) and radial maze performance (between 7.5 and 8.5 months post-grafting). One month after completion of behavioral testing, the dorsal hippocampi of these rats were prepared for measuring choline acetyltransferase (ChAT) activity and high affinity synaptosomal uptake of both [3H]choline and [3H]serotonin. The remaining rats were used for histological verifications on brain sections stained for acetylcholinesterase (AChE). The lesions increased locomotor activity, impaired radial maze learning and, in the dorsal hippocampus, reduced AChE positive staining, decreased ChAT activity (-73%) as well as high affinity uptake of both choline (-81%) and serotonin (-82%). Neither type of transplant produced any significant behavioral recovery. However, septal transplants increased hippocampal AChE positivity, restored ChAT activity and enhanced choline uptake to 116% and 70% of the values found in sham-operated rats, respectively; they had no significant effect on uptake of serotonin. Transplants from the raphe region had weak effects on hippocampal AChE positivity, increased both the ChAT activity and the choline uptake to 70% ad 38% of the sham-operated rats, respectively, and produced an (over)compensation of the serotonin uptake which reached 324% of the values found in sham-operated rats. The co-transplantation of both regions resulted in restoration of ChAT activity (113% of sham-operated rats values), choline uptake (83% of sham-operated rats) and serotonin uptake (129% of sham-operated rats). Our neurochemical data show that after extensive denervation of the hippocampus, intrahippocampal grafts of fetal neurons may foster a neurotransmitter-specific recovery which depends upon the anatomical origin of the grafted cells: a graft rich in serotonergic neurons overcompensates the serotonergic deficit, a graft rich in cholinergic neurons attenuates the cholinergic deficit, whereas a mixture of both types of grafts produces recovery from both types of deficits. Thereby, both the feasibility and the interest of the co-grafting technique are confirmed.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2000

Effect of oral CDP-choline on plasma choline and uridine levels in humans.

Twelve mildly hypertensive but otherwise normal fasting subjects received each of four treatments in random order: CDP-choline (citicoline; 500, 2000, and 4000 mg) or a placebo orally at 8:00 a.m. on four different treatment days. Eleven plasma samples from each subject, obtained just prior to treatment (8:00 a.m.) and 1-12 hr thereafter, were assayed for choline, cytidine, and uridine. Fasting terminated at noon with consumption of a light lunch that contained about 100 mg choline. Plasma choline exhibited dose-related increases in peak values and areas under the curves (AUCs), remaining significantly elevated, after each of the three doses, for 5, 8, and 10 hr, respectively. Plasma uridine was elevated significantly for 5-6 hr after all three doses, increasing by as much as 70-90% after the 500 mg dose, and by 100-120% after the 2000 mg dose. No further increase was noted when the dose was raised from 2000 to 4000 mg. Plasma cytidine was not reliably detectable, since it was less than twice blank, or less than 100 nM, at all of the doses. Uridine is known to enter the brain and to be converted to UTP; moreover, we found that uridine was converted directly to CTP in neuron-derived PC-12 cells. Hence, it seems likely that the circulating substrates through which oral citicoline increases membrane phosphatide synthesis in the brains of humans involve uridine and choline, and not cytidine and choline as in rats.

Administration, Oral↗

PubMed1978

The relationship of choline and carnitine in the choline deficient rat.

Levels of carnitine in choline deficient and choline supplemented rats were measured in heart, skeletal muscle, plasma, and liver after various treatments. A decreased hepatic concentration of carnitine was shown to be closely correlated to the deficiency in dietary choline. No change in the concentration of plasma ketone bodies after a 48 hour fast was observed in the choline deficient rats when compared to choline supplemented controls, even though the level of hepatic carnitine subsequent to the fast was lower in the deficient rats. The concentration of hepatic carnitine was increased to normal values 1.5 hours after a single injection of 100 mumoles of choline, but was not affected by other "methyl" donors. From experiments presented in this communication it is concluded that the increase in hepatic carnitine is probably due to increased transport and uptake of this compound into the liver rather than by "de novo" synthesis.

Animals↗

PubMed1992

Effects of choline and quiescence on Drosophila choline acetyltransferase expression and acetylcholine production by transduced rat fibroblasts.

Rat-1 fibroblasts were transduced to express Drosophila choline acetyltransferase. The presence of an active enzyme in these cells (Rat-1/dChAT) was confirmed using various methods. Rat-1/dChAT fibroblasts released acetylcholine (ACh) into the culture medium. Moreover, intra- and extracellular levels of ACh could be increased by adding exogenous choline chloride. In addition, serum starvation or confluence-induced quiescence caused an 80% decrease in recombinant choline acetyltransferase activity (compared with actively growing cells). ACh release was also repressed in quiescent fibroblast cultures. Exogenous choline could mitigate the decrease in ACh release. These results indicate that Rat-1 fibroblasts can be genetically modified to produce ACh and that ACh release can be controlled by introducing choline into the culture medium. Furthermore, these data demonstrate that the expression of the retroviral promoter used in this study decreases with the onset of quiescence; however, exogenous choline can increase the amount of ACh released by quiescent fibroblasts.

Acetylcarnitine↗

PubMed1990

Changes in choline acetyltransferase activity and high-affinity choline uptake, but not in acetylcholinesterase activity and muscarinic cholinergic receptors, in rat somatosensory cortex after sciatic nerve injury.

Selected cholinergic markers (choline acetyltransferase, acetylcholinesterase, muscarinic acetylcholine receptor, high-affinity choline uptake) were studied in the hindlimb representation areas of the rat somatosensory cortex and within the visual cortex 1 to 63 days after unilateral transection of the sciatic nerve. In the contralateral somatosensory cortex, peripheral deafferentation resulted in a significant reduction of choline acetyltransferase activity (by 15%) 3 days after sciatic nerve injury, and in a significant reduction of high-affinity choline uptake (by 30%) 1 day after nerve transection, in comparison to untreated control rats. Investigations in individual cortical layers revealed that the decrease of both choline acetyltransferase activity and high-affinity choline uptake sites was mainly due to reductions in cortical layer V. Acetylcholinesterase activity and [3H]quinuclidinyl benzilate binding to muscarinic acetylcholine receptors were not affected by unilateral transection of the sciatic nerve. In the ipsilateral somatosensory cortex, as well as in the visual cortex at both cortical hemispheres, no significant changes in the cholinergic parameters studied could be detected. The data indicate that peripheral deafferentation of the somatosensory cortex results in a transient change of presynaptic cholinergic parameters within the affected somatosensory area as early as 1 to 3 days after the lesion; thus, they emphasize the involvement of cholinergic mechanisms in cortical reorganizational events.

Acetylcholinesterase↗

PubMed1994

Traumatic brain injury reduces hippocampal high-affinity [3H]choline uptake but not extracellular choline levels in rats.

Hippocampal cholinergic hypofunction may contribute to memory deficits following experimental traumatic brain injury. These studies examined two important factors in acetylcholine synthesis: choline availability and neuronal uptake. No reductions in basal extracellular choline levels, using microdialysis, were observed 2 weeks after cortical impact injury. However, studies of high affinity [3H]choline uptake in the hippocampus, measured in a synaptosomal preparation, found a reduction in the maximum velocity of choline uptake (Vmax), while no differences in affinity constants (Km) were found. The results suggest that post-traumatic cholinergic deficits are not attributable to decreased availability of choline, but may be associated with either a decreased ability of cholinergic neurons to take up choline and/or a loss of cholinergic neurons.

Acetylcholine↗

PubMed1987

A comparative study of high affinity choline uptake and choline utilization in cholinergic and non-cholinergic tissues.

Comparative studies of [3H]choline accumulation were done in the Limulus corpora pedunculata, abdominal ganglia and cardiac ganglion. Dual uptake processes for choline were found in all three tissues. In acute experiments, the corpora pedunculata high affinity choline uptake system showed exclusive sensitivity to ouabain. Prolonged exposure to ouabain revealed that the HAChUS of all three tissues were significantly inhibited. The metabolism of [3H]choline transported via the high affinity process in the three tissues was studied. [3H]Acetylcholine was a major product of the [3H]choline taken up by the corpora pedunculata and the abdominal ganglia. Phosphorylcholine was the major product seen in cardiac ganglion extracts and occurred in significant proportions in abdominal ganglia extracts. [3H]Acetylcholine was not detected in cardiac ganglion extracts. Treatment with either lithium chloride or hemicholinium-3 markedly inhibited high affinity uptake of [3H]choline in all three tissues.

Animals↗

PubMed2004

The trimethylammonium headgroup of choline is a major determinant for substrate binding and specificity in choline oxidase.

Choline oxidase catalyzes the oxidation of choline to glycine betaine via two sequential flavin-linked transfers of hydride equivalents to molecular oxygen and formation of a betaine aldehyde intermediate. In the present study, choline and glycine betaine analogs were used as substrates and inhibitors for the enzyme to investigate the structural determinants that are relevant for substrate recognition and specificity. Competitive inhibition patterns with respect to choline were determined for a number of substituted amines at pH 6.5 and 25 degrees C. The Kis values for the carboxylate-containing ligands glycine betaine, N,N-dimethylglycine, and N-methylglycine increased monotonically with decreasing number of methyl groups, consistent with the trimethylammonium portion of the ligand being important for binding. In contrast, the acetate portion of glycine betaine did not contribute to binding, as suggested by lack of changes in the Kis values upon substituting glycine betaine with inhibitors containing methyl, ethyl, allyl, and 2-amino-ethyl side chains. In agreement with the inhibition data, the specificity of the enzyme for the organic substrate (kcat/Km value) decreased when N,N-dimethylethanolamine, N-methylethanolamine, and the isosteric substrate 3,3-dimethyl-1-butanol were used as substrate instead of choline; a contribution of approximately 7 kcal mol(-1) toward substrate discrimination was estimated for the interaction of the trimethylammonium portion of the substrate with the active site of choline oxidase.

Alcohol Oxidoreductases↗

PubMed1993

Phorbol myristate acetate stimulates [3H]choline incorporation into phosphatidylcholine independently of the 'de novo' pathway in Krebs-II ascitic cells: a unique effect of phorbol ester on choline uptake.

The effect of phorbol 12-myristate 13-acetate (PMA) on [3H]choline incorporation into phosphatidylcholine (PtdCho) and on the 'de novo' pathway of PtdCho synthesis has been investigated, compared with that of oleic acid, in ascitic-strain Krebs-II cells. Both compounds stimulated [3H]choline incorporation into PtdCho, but the PMA-induced incorporation was saturable at concentrations of the agonist around 100 nM, whereas no saturation was noticed with oleic acid up to 1 mM. Chase experiments showed no effect of PMA on the conversion of phosphocholine into CDP-choline. The phorbol ester did not stimulate any of the enzyme activities of the 'de novo' pathway, whereas oleic acid increased specifically by 2.5-fold the CTP:phosphocholine cytidylyltransferase (CT, EC 2.7.7.15) activity. In addition, no change in the subcellular distribution of CT was observed upon incubation with PMA, in contrast with oleic acid treatment. Cells challenged with oleic acid showed a 25-fold increase in diradylglycerol (DG) content, which was not modified upon incubation with 200 nM PMA, the most effective concentration of phorbol ester promoting choline incorporation. Subcellular fractionation of Krebs-II cells on Percoll gradients revealed that [3H]PMA and 1-radyl-2-[3H]oleoyl-glycerol, derived from exogenously supplied [3H]oleic acid, both exhibited the same enrichment in the endoplasmic reticulum. We have previously shown that the labelled fatty acid also accumulated in the endoplasmic reticulum [Tercé, Record, Tronchère, Ribbes and Chap (1992) Biochem. J. 282, 333-338]. However, PMA induced a stimulation of choline uptake, which was not provoked by PMA 4-O-methyl ether, which interacts poorly with protein kinase C. Our data provide evidence that the enhancement of [3H]choline incorporation into PtdCho triggered by PMA and oleic acid proceeds via completely distinct mechanism(s).

Animals↗

PubMed2005

Inhibition of choline uptake by N-cyclohexylcholine, a high affinity ligand for the choline transporter at the blood-brain barrier.

The blood-brain barrier (BBB) choline transporter (CHT) may have utility as a drug delivery vector for drugs that act in the central nervous system. Previous studies suggested the importance of hydrophobic moieties on the cationic nitrogen of choline for improved affinity for this transporter. In a pilot study, we therefore designed five novel N-cycloalkyl derivatives of choline, one of which showed promising inhibition properties. This choline analogue had a cyclohexyl (UMBB-5) moiety substituting one of the methyl groups attached to the cationic nitrogen in choline. In situ experimental data were obtained from in situ rat brain perfusion studies. The binding affinity for the BBB-choline transporter found for UMBB-5 was K(i)=1.9 microM. Comparative molecular field analysis (CoMFA) suggested that the cyclohexyl moiety orientates towards a steric favourable area. Taken together, the results of these in situ and in silico studies provide further evidence or restrictions that occur with binding to this brain drug delivery vector.

Animals↗

PubMed1972

Effect of chemical sympathectomy on the content of acetylcholine, choline and choline acetyltransferase activity in the cat spleen and iris.

1. Acetylcholine and choline were measured in the spleens and irides of normal and 6-hydroxydopamine-treated cats. In addition, choline acetyltransferase activity was measured in the spleens.2. No acetylcholine or choline acetyltransferase activity were found in spleens of normal or treated cats. The choline content of normal spleens was 12.4 +/- 1.5 mug/g wet wt. (mean +/- S.E. of mean), which was not significantly altered by chemical sympathectomy.3. The acetylcholine and choline contents of the cat iris were 3.0 +/- 0.3 mug/g wet wt. and 7.7 +/- 0.9 mug/g wet wt., respectively. There was no difference in acetylcholine and choline concentrations between left and right or normal and sympathectomized irides.4. These results are discussed in relation to the question of a cholinergic link in post-ganglionic sympathetic transmission.

Acetylcholine↗

PubMed1984

Complete purification of choline kinase from rat kidney and preparation of rabbit antibody against rat kidney choline kinase.

Choline kinase was purified from rat kidney to apparent homogeneity with respect to both native and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified enzyme showed a minimum molecular weight of 42,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. On the other hand, the molecular size of 75,000-80,000 was estimated through Sephadex G-150 gel filtration, indicating that the enzyme in rat kidney exists most likely in a dimeric form. Specific antibody was raised in rabbit against the highly purified rat kidney choline kinase protein, then immunochemical cross-reactivity was investigated between rabbit antiserum and choline kinase preparations from various rat tissues. The antiserum inhibited choline kinase activity almost completely in the crude preparation not only from kidney but also from lung, intestine, and normal untreated liver cytosol, but it could inhibit only partially the activity from either 3-methylcholanthrene- or carbon tetrachloride-induced rat liver cytosol. The overall results demonstrated that, although choline kinase protein appears to exist in multiple forms in rat tissues, most of them are immunochemically identical, and that either 3-methylcholanthrene- or carbon tetrachloride-inducible form(s) of choline kinase in rat liver could be quite different from a form or forms existing in normal untreated rat liver cytosol.

Animals↗

PubMed1994

N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulphonamide (H-89) inhibits incorporation of choline into phosphatidylcholine via inhibition of choline kinase and has no effect on the phosphorylation of CTP:phosphocholine cytidylyltransferase.

We have shown previously that N-[2-bromocinnamyl(amino)-ethyl]-5-isoquinolinesulphonamide (H-89), a selective inhibitor of cyclic-AMP-dependent protein kinase (PKA), inhibits phosphatidylcholine biosynthesis in HeLa cells. In the present study, we elucidated the mechanism underlying the described inhibition. Treatment of cells with 10 microM H-89 had no effect on the phosphorylation of CTP:phosphocholine cytidylyltransferase. However, H-89 slightly affected the distribution of cytidylyltransferase between cytosol and membranes, but the cellular 1,2-diacylglycerol content was not influenced. Furthermore, pulse-chase experiments revealed that H-89 did not affect cytidylyltransferase activity. Instead, H-89 inhibited choline kinase, the enzyme catalysing the first step in the CDP-choline pathway. In the presence of 10 microM H-89, choline kinase activity was inhibited by 36 +/- 7.6% in vitro. Additionally, the phosphorylation of choline to phosphocholine was inhibited by 30 +/- 3% in cell-culture experiments. This inhibitory effect could be partly prevented by simultaneous addition of 10 microM forskolin, indicating that choline kinase is regulated in part by PKA activity.

Cell Membrane↗

PubMed1984

Effects of insulin and hydrocortisone on lung tissue phosphatidyl choline and disaturated phosphatidyl choline in fetal rabbits in vivo.

To determine the effects of insulin and hydrocortisone on lung tissue surfactant, the fetuses of New Zealand White rabbits were injected with insulin, saline (0.154 mol/l), insulin+hydrocortisone, insulin+saline or saline+hydrocortisone, or were sham-operated on day 27 of gestation. Twenty-four hours later (on day 28 of gestation) delivery was accomplished by Caesarian hysterectomy. The lung tissues were analysed for phosphatidyl choline and disaturated phosphatidyl choline. Both were higher in fetuses injected with insulin than in sham-operated control animals. The phosphatidyl choline and disaturated phosphatidyl choline were also higher in the fetuses injected with insulin+hydrocortisone than in fetuses injected with insulin or hydrocortisone alone. These results suggest that insulin increases the phosphatidyl choline and disaturated phosphatidyl choline content in lung tissue in fetal rabbits in vivo, and that in the presence of hydrocortisone, insulin appears to have an additive effect.

Animals↗