Choline uptake

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

The reaction of choline with mitochondrial bound acetylcoenzyme A is catalysed by the cytoplasmic enzyme choline acetyltransferase (ChAT) (see Fig. 6.1). ChAT itelf is synthesised in the rough endoplasmic reticulum of the cell body and transported to the axon terminal. Although the precise location of the synthesis of ACh is uncertain most of that formed is stored in vesicles. It appears that while ChAT is not saturated with either acetyl-CoA or choline its synthesising activity is limited by the actual availability of choline, i.e. its uptake into the nerve terminal. No inhibitors of ChAT itself have been developed but the rate of synthesis of ACh can, however, be inhibited by drugs like hemicholinium or triethylcholine, which compete for choline uptake into the nerve. 

ACh is widely distributed throughout the brain and parts of the spinal cord (ventral horn and dorsal columns). Whole brain concentrations of lOnmolg" tissue have been reported with highest concentrations in the interpeduncular, caudate and dorsal raphe nuclei. Turnover figures of 0.15-2.0 nmol g min vary with the area studied and the method of measurement, e.g. synthesis of labelled ACh from [ " C]-choline uptake or rundown of ACh after inhibition of choline uptake by hemicholinium. They are all sufficiently high, however, to suggest that in the absence of synthesis depletion could occur within minutes. 

Low concentrations of solubilised jS-albumin inhibit ACh release in slices from rat hippocampus and cortex areas which show degeneration in AzD, but not in slices from the striatum which is unaffected. While not totally specific to ACh, since some inhibition of NA and DA and potentiation of glutamate release have been reported, this effect is achieved at concentrations of A/i below those generally neurotoxic. Since jS-amyloid can inhibit choline uptake it is also possible (see Auld, Kar and Quiron 1998) that in order to obtain sufficient choline for ACh synthesis and the continued function of cholinergic neurons, a breakdown of membrane phosphatidyl choline is required leading to cell death (so-called autocannibalism), /i-amyloid can also reduce the secondary effects of Mi receptor activation such as GTPase activity... 

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Benishin, C. G. (1992). Actions of ginsenoside Rb on choline uptake in central cholinergic nerve endings. Neurochem. Int. 21,1-5. 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

Metting TL, Burgio DE, Terry AV Jr, Beach JW, McCurdy CR, Allen DD. (1998). Inhibition of brain choline uptake by isoarecolone and lobeline derivatives implications for potential vector-mediated brain drug delivery. Neurosci Lett. Dec. 11 258(1) 25-28. 

Decker MW, Pelleymounter MA, Gallagher M. (1988). Effects of training on a spatial memory task on high affinity choline uptake in hippocampus and cortex in young adult and aged rats. J Neurosci. 8(1) 90-9. 

Kristofikova Z, Benesova 0, Tejkalova H. (1992). Changes in high-affinity choline uptake in the hippocampus of old rats after long-term administration of two nootropic drugs (tacrine and Ginkgo biloba extract). Dementia. 3 304-7. 

Herzog C, Gahndi C, Bhattacharya P, Walsh TJ. 2000. Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-afhnity choline uptake in the hippocampus. Neurobiology of Learning and Memory 73 168-179. 

Studies of animals with central cholinergic lesions produced by either pharmacological inhibition of choline uptake or direct excitotoxic lesions of basal forebrain cholinergic neurons have shown highly specific attentional deficits (Muir et al. 1992 Robbins et al. 1989). These animals showed deficits that might be predicted from studies of humans with AD that is, they showed increased response latency and increased responsiveness to irrelevant sensory stimuli. Studies by Vidal (1994b) have shown that administration of a nicotinic antagonist into rat prefrontal cortex impairs performance on spatial... 

Simon JR, Kuhar MJ High affinity choline uptake ionic and energy requirement. J Neurochem 27 93-99, 1976... 

Diethanolamine has been shown to inhibit choline uptake into cultured Syrian hamster embryo (SHE) and Chinese hamster ovary cells and to inhibit the synthesis of phosphatidylcholine in in-vitro systems in a concentration-dependent, competitive and reversible manner (Lehman-McKeeman Gamsky, 1999, 2000). Diethanolamine treatment caused a marked reduction in hepatic choline metabolite concentrations in mice following two weeks of dermal dosing. The most pronounced reduction was in the hepatic concentration of phosphocholine, the intracellular storage form of choline (Stott et al, 2000). Moreover, the pattern by which choline metabolites were altered was similar to the pattern of change that has been observed following dietary choline deprivation in rodents (Pomfret et al, 1990). Excess choline also prevented diethanolamine-induced inhibition of phosphatidylcholine synthesis and incorporation of diethanolamine into SHE cell phospholipids (Lehman-McKeeman Gamsky, 2000). 

Lehman-McKeeman, L.D. Gamsky, E.A. (1999) Diethanolamine inhibits choline uptake and phosphatidylcholine synthesis in Chinese hamster ovary cells. Biochem. biophys. Res. Comm., 262, 600-604... 

EGb inhibits the uptake of [3H]norepinephrine ([3H]NE) and [3H]dopamine and [3H]5-hydroxytryptamine ([3H]5-HT) into in vitro synaptosomes prepared from the striatum and cortex in a concentration-dependent manner. The rank order of potency for the inhibition of amine uptake is NE > dopamine > 5-HT [173]. Similar results were obtained by Ramassamy et al. [174]. These workers showed that EGb decreased the specific uptakes of [3H]dopamine, [3H]5-HT and [3H]choline by synaptosomes prepared from the striatum of mice in a concentration-dependent manner. The IC,0 values were 637 pg/rol for [3H]dopamine uptake, 803 pg/ml for [3H]5-HT uptake, >2000 pg/ml for [3H]choline uptake. However, they concluded that the inhibition of amine uptake caused by EGb appears to be non-specific, since EGb also prevents the specific binding of the dopamine uptake inhibitor [3H]GBR12783 to membranes prepared from striatum. 

Reduction of choline uptake into the brain of older adults may be a contributing factor to late life onset of neurodegenerative, particularly... 

Reduced choline uptake and acetylcholine synthesis. Loss of cells in nucleus basalis and occurrence of tangles in remaining cells in the brain area Decreased dopamine beta-oxidase and reduced noradrenaline synthesis. Loss of cells in the locus coeruleus and occurrence of tangles in remaining cells Slight reduction in dopamine... 

Mechanism of action Mechlorethamine is transported into the cell by a choline uptake process. The drug loses a chloride ion and forms a reactive intermediate that alkylates the N7 nitrogen of a... 

Whalley, C.E., Shih, T.M. (1989). Effects of soman and sarin on high affinity choline uptake by rat brain synaptosomes. Brain Res. Bull. 22 853-8. 

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