Choline acetylcholine synthesis

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,... 

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... 

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. 

In contrast to the biosynthetic systems for catecholamines and serotonin discussed earlier, there appear to be no posttranslational modifications such as protein phosphorylation or proteolytic activation that regulate the catalytic state of choline acetyltransferase. A more detailed discussion of acetylcholine synthesis may be found in Blusztajn and Wurtman (1983). 

Molecular Properties of Choline Acetyltransferase and Their Importance for the Compartmentation of Acetylcholine Synthesis... 

A major approach to the treatment of AD has involved attempts to augment the cholinergic function of the brain. An early approach was the use of precursors of acetylcholine synthesis, such as choline chloride and phosphatidyl choline (lecithin). Although these supplements generally are well tolerated, randomized trials have failed to demonstrate any clinically significant efficacy. 

Levenler, S. M., Rowell, P. P, and Clark. M. J. (1982). The effect of choline acetyltransfcrasc inhibition on acetylcholine synthesis and release in tenti hutnan placenta. J. Pharmacol Exp. Ther. 222, 301-305. 

Fig. 5-1. Diagram of neuromuscular conduction, (a) Nerve fiber with axon terminal in synaptic trough of muscle. (b) Close-up of axon terminal in trough, with synaptic vesicles indicated. (c) Acetylcholine synthesis from acetate and choline and storage of acetylcholine in synaptic vesicles, (d) Release of acetylcholine from synaptic vesicles after an action potential. (e) Acetylcholine stimulation of endplate at receptor for site, (f) Hydrolysis of acetylcholine by membrane-bound acetylcholinesterase. Reprinted with permission from Clinical Symposia. 1(1, 8) 162, Plate 3118. West Caldwell, NJ CIBA GEIGY Medical Education Division.

Jope, R. S. (1979). High affinity choline transport and acetyl coenzyme A production and their roles in the regulation of acetylcholine synthesis. Brain Res. Rev., 1, 313-44. 

Choline Acetylcholine receptors Synthesis, depolarization of neuromuscular junction 25,26... 

It is unlikely that choline acetyltransferase in brain is saturated with either of its substrates, so that choline (and possibly acetyl-CoA) availability determines the rate of acetylcholine synthesis. Under conditions of rapid neuronal firing acetylcholine release by brain neurons can be directly altered by dietary intake of choline. Based on this observation, choline has been used as a possible memory-... 

Acetylcholine Precursors. Early efforts to treat dementia using cholinomimetics focused on choline [62-49-7] (12) supplement therapy (Fig. 3). This therapy, analogous to L-dopa [59-92-7] therapy for Parkinson s disease, is based on the hypothesis that increasing the levels of choline in the brain bolsters acetylcholine (ACh) synthesis and thereby reverses deficits in cholinergic function. In addition, because choline is a precursor of phosphatidylcholine as well as ACh, its supplementation may be neuroprotective in conditions of choline deficit (104). 

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)...

The answers are 333-c, 334-a, 335-d. (Katzung, pp 77-80. Hardman, pp 116, 132, 147—148.) Acetylcholine is synthesized from acetyl-CoA and choline. Choline is taken up into the neurons by an active transport system. Ilemicholinium blocks this uptake, depleting cellular choline, so that synthesis of ACh no longer occurs. 

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