Acetylcholine , synthesis

Relations between Acetylcholine Synthesis and Metabolism of Carbo-... 

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,... 

Figure 14.1. Outline of the relationship between glucose metabolism, acetylcholine synthesis and energy production. TCA = tricarboxylic acid ADP = adenosine diphosphate P = inorganic phosphate.

Figure 2.14 Iriter-relationship between intermediary. metabolism of glucose, phospholipids and acetylcholine synthesis. Acetyl CoA acetyl coenzyme A CAT-catechol-O-methyltransferase AChE acetylcholinesterase.

Drugs which enhance the activity of the central cholinergic system have been shown to have antimanic effects. Experimental studies have shown that lithium increases acetylcholine synthesis in the cortex, which is... 

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

Rapin et al. [11] have reported an increase of the acetylcholine synthesis rate constant evaluated by a bolus injection of [3H]choline in the hippocampus of 4-month-old rats after acute administration of EGb (100 mg/kg Lp.). Similar results were obtained in the frontal cortex, hippocampus and corpus striatum after chronic treatment with EGb (100 mg/kg/day p.o. for 21 days). On the other hand, the acetylcholine turnover rate was not modified by either acute or chronic administration of EGb. These results indicate that EGb might increase acetylcholine release. 

Acetylcholine synthesis. Acetylcholine (ACh) is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA) (Fig. 12—8). Choline is derived from dietary and intraneuronal sources, and AcCoA is synthesized from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase to produce the neurotransmitter ACh. 

Acetylcholine is destroyed too quickly and completely by AChE to be available for transport back into the presynaptic neuron, but the choline that is formed by its breakdown can be transported back into the presynaptic cholinergic nerve terminal by a transporter similar to the transporters for other neurotransmitters discussed earlier in relation to norepinephrine, dopamine, and serotonin neurons. Once back in the presynaptic nerve terminal, this choline can be recycled into acetylcholine synthesis (Fig. 12—8). 

Matthies DS, Fleming PA, Wilkes DM, Blakely RD (2006) The Caenorhabditis elegans choline transporter CHO-1 sustains acetylcholine synthesis and motor function in an activity-dependent manner. J Neurosci 26 6200-6212. 

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... 

More recently Braganca, Faulkner, and Quastel (B15) showed that this inhibition of acetylcholine synthesis in brain slices by ammonia is consistent only in the diminution of bound acetylcholine. They further showed that the addition of inhibitors of glutamine synthesis, such as methionine sulfoxide, ethionine sulfoxide, and methionine sulfoximine (the toxic product, causing convulsions, formed in flour chemically aged with nitrogen trichloride) would partially reverse the ammonium inhibition. These observations were confirmed and extended to a wide variety of ATP-requiring reactions by Weil-Malherbe. In support of this suggestion was the observation that ammonia is taken up by the brain in hepatic coma (B8). The observations are valid and have been confirmed, but the interpretation of the data and the hypothesis are questionable. A quantitative basis for the evaluation of this mechanism can... 

B15. Braganca, B. J., Faulkner, P., and Quastel, J. H., Effects of inhibitors of glutamine synthesis on inhibition of acetylcholine synthesis in brain slices by ammonium ions. Biochim. et Biophys. Acta 10, 83 (1953). 

Hoshi, M., Takashima, A., Murayama, M., Yasutake, K., Yoshida, N., Ishiguro, K., Hoshino, T., Imahori, K. Nontoxic amyloid beta peptide 1-42 suppresses acetylcholine synthesis. Possible role in cholinergic dysfunction in Alzheimer s disease. 

Biagioni S, Tata AM, De Jaco A, and Augusti-Tocco G (2000) Acetylcholine synthesis and neuron differentiation. International Journal of Developmental Biology 44,689-97. 

Gerster H (1996) The importance of vitamin B6 for development of the infant. Human medical and animal Experimental studies. Z Emahrungswiss 35(4) 309-317 Gibson GE, Blass JP (1985) Oxidative metabolism and acetylcholine synthesis during acetylpyri-dine treatment. Neurochem Res 10(4) 453-467... 

Choline alfoscerate increases cerebral acetylcholine synthesis and release (1). In the light of animal studies it has been investigated as a possible treatment for vascular dementia (2). Adverse effects have been few, notably headache and flushing. 

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