High-affinity choline uptake

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,... 

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. 

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

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. 

Keywords Neurodegenerative diseases Alzheimer s disease Parkinson s disease Cholinergic hypothesis Muscarinic agonists Muscarinic antagonists Nicotinic agonists Acetylcholine releasers Acetylcholinesterase inhibitors High affinity choline uptake enhancers... 

Despite the drawbacks of the cholinergic hypothesis, this idea has guided most of the researchers involved with AD and enormous resources have been invested in developing compounds that would directly (nicotinic and M, selective muscarinic agonists) or indirectly (acetylcholinesterase inhibitors, M2 selective muscarinic antagonists, acetylcholine releasers, high affinity choline uptake inhibitors) increase the level of cholinergic transmission in the brain. 

K. -I., S., Egawa, M., Tobe, A., Morinaka, Y., 1995. Design and synthesis of 4-acylaminopyridine derivatives novel high affinity choline uptake enhancers 11. Bioorg. Med. Chem. Lett. 5, 1495-1500. 

Klemin, N., and Kuhar, M, J. (1979). Post-mortem changes in high affinity choline uptake. J. Neitrochem. 32, 1487-1494,... 

Simon, J. R, Atweh, S and Kuhar, M. J. (1976). Sodium-dependent high affinity choline uptake A regulatory step in the synthesis of acetylcholine. J. Neurochem. 26, 909-922. 

ACh synthesis. The precursors of the ACh are the choline (Ch) and the acetyl coenzyme A (Ac-CoA). The reversible formation of ACh is catalysed by the choline acetyltransferase (ChAT EC 2.3.1.6). Since the enzyme has both cytoplasmic and membrane-bound forms, consequently the synthesis can take place by two different mechanisms. The synthesis can be influenced by the formation reactions of the precursors and by their transport to the place of the synthesis. Both the sodium-dependent high affinity choline uptake (Barker Mittag, 1975) and the transport of the mitochondrial Ac-CoA to the cytoplasm (Jope, 1979) may be the rate-limiting step of the synthesis. 

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