Choline Acetyltransferase

Choline acetyltransferase catalyzes the synthesis of ACh—the acetylation of choline with acetyl coenzyme A (CoA). Choline acetyltransferase, like other protein constituents of the neuron, is synthesized within the perikaryon and then is transported along the length of the axon to its terminal. Axonal terminals contain a large number of mitochondria, where acetyl CoA is synthesized. Choline is taken up from the extracellular fluid into the axoplasm by active transport. The synthetic step occurs in the cytosol; most of the ACh is then sequestered within synaptic vesicles. Inhibitors of choline acetyltransferase have no therapeutic utility, in part because the uptake of choline, not the activity of the acetyltransferease, is rate-limiting in ACh biosynthesis.

CHOLINE TRANSPORT Transport of choline from the plasma into neurons is rate-limiting in ACh synthesis and is accomplished by distinct high- and low-affinity transport systems. The high-affinity system (Km = 1-5 m-M) is unique to cholinergic neurons, dependent on extracellular Na+, and inhibited by hemicholinium. Plasma concentrations of choline approximate 10 mM. Much of the choline formed from AChE-catalyzed hydrolysis of ACh is recycled into the nerve terminal.

STORAGE OF ACh

After its synthesis, ACh is taken up by storage vesicles principally at the nerve terminals. The vesicles contain both ACh and ATP, at an estimated ratio of 10:1, in the fluid phase with Ca2+ and Mg2+, and vesiculin, a negatively charged proteoglycan thought to sequester Ca2+ or ACh. In some cholinergic vesicles there are peptides (e.g., VIP) that act as cotransmitters. The vesicular ACh transporter, has considerable concentrating power, is saturable, and is ATP-dependent. The process is inhibited by vesamicol (Figure 6-3). Inhibition by vesamicol is noncompetitive and reversible and does not affect the vesicular ATPase. Estimates of the ACh content of synaptic vesicles range from 1000 to over 50,000 molecules per vesicle; a single motor nerve terminal contains 300,000 or more vesicles.

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