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Figure 11.5 |
Choline acetyltransferase (CAT): As shown in Figure 11.5, ACh is synthesized by a single step reaction catalyzed by the biosynthetic enzyme choline acetyltransferase. As is the case for all nerve terminal proteins, CAT is produced in the cholinergic cell body and transported down the axon to the nerve endings. Both CAT and ACh may be found throughout the neuron, but their highest concentration is in axon terminals. The presence of CAT is the "marker" that a neuron is cholinergic, only cholinergic neurons contain CAT.
The rate-limiting steps in ACh synthesis are the availability of choline and acetyl-CoA. During increased neuronal activity the availability of acetyl-CoA from the mitochondria is upregulated as is the uptake of choline into the nerve ending from the synaptic cleft. Ca2+ appears to be involved in both of these regulatory mechanisms. As will be described later, the inactivation of ACh is converted by metabolism to choline and acetic acid. Consequently much of the choline used for ACh synthesis comes from the recycling of choline from metabolized ACh. Another source is the breakdown of the phospholipid, phosphatidylcholine. One of the strategies to increase ACh neurotransmission is the administration of choline in the diet. However, this has not been effective, probably because the administration of choline does not increase the availability of choline in the CNS.
The majority of the ACh in nerve endings is contained in clear (as viewed in the electron microscope) 100 um vesicles. A small amount is also free in the cytosol. Vesicle-bound ACh is not accessible to degradation by acetylcholinesterase (see below).
The uptake of ACh into storage vesicle occurs through an energy-dependent pump that acidifies the vesicle. The acidified vesicle then uses a vesicular ACh transporter (VAChT) to exchange protons for ACh molecules. No useful pharmacological agents are available to modify cholinergic function through interaction with the storage of ACh.
Interestingly, the gene for VAChT is contained on the first intron of the choline acetyltransferase gene. This proximity implies the two important cholinergic proteins are probably regulated coordinately.
Figure 11.6 |
The release of ACh occurs through Ca2+ stimulated docking, fusion, and fission of the vesicle with the nerve terminal membrane, as discussed previously.
You will recall that the miniature endplate potentials and the quantal release in response to action potentials at the neuromuscular junction are due to the release of packets of ACh from individual storage vesicles (Chapter 5). Many toxins are known that interfere with these processes and are effective in preventing ACh secretion. The examples in Figure 11.6 shows botulinum toxin inhibition and black widow spider venom (BWSV) stimulation of ACh release.
Figure 11.7 |
