Acetylcholine ACh , synthesis

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)...

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,... 

The process of neuromuscular transmission includes the synthesis and storage of acetylcholine (ACh), its release and passage across the synaptic cleft, the interaction with nicotinic ACh receptor, and the process of actual muscle contraction. 

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. 

Effects of triethyllead acetate on the cholinergic system in the brain of the rats were investigated in vitro. At concentrations below 0.1 pM it inhibited the depolarized release of acetylcholine (ACh) from slices of cortex and the synthesis of ACh, while the non-depolarized release of ACh was potent in a dose-dependent manner135. 

Figure 17-6 Ordered synthesis of acetylcholine (ACh) by choline acetyltransferase (ChAT).

Choline acetyltransferase (ChAc) is responsible for the synthesis of the chemical transmitter acetylcholine (ACh) and is therefore an important enzyme in nervous tissue. There is an excellent correlation between the level of ACh and the level of ChAc in different parts of the nervous system (Silver, 1967), indicating that this enzyme governs the level of ACh. The localization of ChAc is therefore synonymous with the site of synthesis of ACh and knowledge of this site gives important information as to the further processes necessary for the uptake and storage of the neurotransmitter. 

Acetylcholine (ACh) Receptor. Several transmembrane or amphipathic sequences are common to all five subunits of the ACh receptor. A 23-residue peptide that corresponds to the transmembrane M2 segment of the Torpedo ACh receptor delta subunit was selected for synthesis and evaluation (241) on the basis of experimental evidence that implicated its proximity to the channel. This peptide formed discrete ionic channels in phosphotidylcholine membranes, in contrast to another ACh receptor trans-... 

Figure 6-2. Characteristics of transmitter synthesis, storage, release, and termination of action at cholinergic and noradrenergic nerve terminals are shown from the top downward. Circles represent transporters ACh. acetylcholine AChE. acetylcholinesterase ChAT, choline acetate transferase DOPA, dihydroxyphenylalanine NE, norepinephrine TCA, tricyclic antidepressant TH, tyrosine hydroxylase.

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. 

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.

---