Cholinergic neurons acetyl-coenzyme

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

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,... 

It is synthesized within the cholinergic neurons by the transfer of an acetyl group from acetyl coenzyme A to the organic base choline. The specific enzyme choline acetylase is essential for this reaction. Coenzyme A is widely distributed in the body and choline acetylase is synthesized in the cell bodies of the cholinergic neurons. 

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. 

Neurochemical examination of biopsy and antopsy brain material from Alzheimer patients has revealed loss of the presynaptic marker enzymes acetyl coenzyme A (acetyl-CoA), chohne 6>-acetyltransferase and acetylcholinesterase (AChE), and of muscarinic receptor sites of the M2 subtype correlating with dementia score and severity of nenrohistopathology [8]. These alterations do, to some extent, reflect the well-documented neuronal cell loss in the nucleus of Meynert in presenile dementia and AD. Lesions of this brain nncleus in rats, a limited model for the cholinergic deficit of AD, resnlt in marked reductions in the levels of cholinergic en me markers in the neocortex accompanied by great decreases in the total muscarinic receptor levels [9,10]. 

Biosynthesis of ACh involves a reversible reaction in which an acetyl group is transferred from acetyl coenzyme A to choline by the enzyme choline acetyltransferase. The rate-limiting step in ACh s)mthesis is the availability of choline, which is transported into neuronal terminals from the extracellular space by sodium-dependent, high-affinity uptake systems. ACh s)mthesized in the cytosol is stored in vesicles via the action of the vesicular ACh transporter. In response to an action potential, vesicular ACh is released by exocytosis from cholinergic nerve terminals, where it can interact with two major types of receptors muscarinic... 

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