Neuron 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). 

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). 

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. 

Patterson, P.H. and Chun, L.L.Y. (1974) The influence of non-neuronal cells on catecholamine and acetylcholine synthesis and accumulation in cultures of dissociated sympathetic neurons. Proc. Natl. Acad. Sci. USA 71 3607-3610. 

Patterson, P.H. and Chun, L.L. (1977) The induction of acetylcholine synthesis in primary cultures of dissociated rat sympathetic neurons, I. Effects of conditioned medium. Dev. Biol. 56 263-280. 

Acetoacetate can be activated to acetoacetyl CoA in the cytosol by an enzyme similar to the acyl CoA synthetases. This acetoacetyl CoA can be used directly in cholesterol synthesis. It also can be cleaved to two molecules of acetyl CoA by a cytosolic thiolase. Cytosolic acetyl CoA is required for processes such as acetylcholine synthesis in neuronal cells. 

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-... 

One limitation of this method is that the specific activity of the radiolabel is progressively diluted as the radiolabelled transmitter is released from neurons and replaced by that derived from unlabelled substrate. This method also assumes that there is no compartmentalisation of the terminal stores, yet there is ample evidence that newly synthesised acetylcholine and monoamines are preferentially released. An alternative approach is to monitor the rate at which the store of neurotransmitter is depleted after inhibition of its synthesis (Fig. 4.1). However, the rate of release of some neurotransmitters (e.g. 5-HT) is partly governed by their rate of synthesis and blocking synthesis blunts release. 

Manns, I. D., Mainville, L. 8r Jones, B. E. (2001). Evidence for glutamate, in addition to acetylcholine and GABA, neurotransmitter synthesis in basal forebrain neurons projecting to the entorhinal cortex. Neuroscience 107, 249-63. 

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. 

In almost all tissues where 5-HT4 receptors are present, 5-HT or any other agonists increase intracellular cAMP synthesis [12], as has been shown for hippocampus, atrium, esophagus, intestinal tissue and adrenal cortex. A number of processes can be triggered by an increase in intracellular cAMP. For instance in the intestine, an increase in intracellular cAMP concentrations following activation of 5-HT4 receptors can trigger a relaxation of the smooth muscle. However, activation of 5-HT4 receptors present on intestinal inter- and motor-neurons leads to a facilitation of acetylcholine release and, thereby, to increased contractions of intestinal smooth muscle [13]. 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

Figure 14.9 Axonal transport of enzymes, neurotransmitter synthesis, storage in vesicles, release and uptake by presynaptic neurone or enzymic degradation. The neurotransmitter in the synaptic cleft may be removed by the presynaptic neurone (i.e. recycling), by the postsynaptic neurone or by glial cells (not shown). Alternatively, the neurotransmitter may be degraded, and therefore inactivated, by enzyme action. For example, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft (Chapter 3). One of the products, choline, is transported back into the neurone to be reacted with acetyl-CoA to re-form acetylcholine. The vesicle, once empty, may also be recycled for re-packaging (Figure 14.8).

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