Transporters of acetylcholine

The first is via hydrolytic destruction by acetylcholinesterase642-645 (pp. 634-637 Eq. 12-25). This esterase and the related butyrylcholinesterase646 are present in the synaptic membrane itself. The second mechanism is energy-dependent transport of acetylcholine into the neuron for reuse. Since much of the transmitter is hydrolyzed, new acetylcholine is synthesized by transfer of an acetyl group of acetyl-CoA to choline.647... 

Varoqui H, Erickson JD (1996) Active transport of acetylcholine by the human vesicular acetylcholine transporter. J Biol Chem 271 27229-27232. 

Choline is taken into the nerve terminal from the synaptic cleft by a sodium-dependent, high-affinity active transport process, which is the rate-limiting step in the biosynthesis of acetylcholine in the nerve terminal (1). In the nerve terminal, choline reacts with acetylcoenzyme A in a process catalyzed by choline acetyltransferase. The acetylcholine thus synthesized is sequestered in the synaptic storage vesicles in the nerve terminal for future use as a neurotransmitter. The active transport of acetylcholine into the storage vesicles has been reviewed (2). Vesamicol (2) at micromolar concentrations blocks transport of acetylcholine into the vesicles (3, 4). 

A number of techniques have been applied to the interface in recent years. For the detailed list and explanations, several reviews are suggested (4-11). Typical evidence of interfacial ion transport is illustrated by Figure 3, where the transport of acetylcholine cation is observed between water and... 

The influx of Ca(Il) across the presynaptic membrane is essential for nerve signal transmission involving excitation by acetylcholine (26). Calcium is important in transducing regulatory signals across many membranes and is an important secondary messenger hormone. The increase in intracellular Ca(Il) levels can result from either active transport of Ca(Il) across the membrane via an import channel or by release of Ca(Il) from reticulum stores within the cell. More than 30 different proteins have been linked to regulation by the calcium complex with calmoduhn (27,28). 

While these functions can be a carried out by a single transporter isoform (e.g., the serotonin transporter, SERT) they may be split into separate processes carried out by distinct transporter subtypes, or in the case of acetylcholine, by a degrading enzyme. Termination of cholinergic neurotransmission is due to acetylcholinesterase which hydrolyses the ester bond to release choline and acetic acid. Reuptake of choline into the nerve cell is afforded by a high affinity transporter (CHT of the SLC5 gene family). 

The synaptic action of acetylcholine is unique among neurotransmitters in that it is terminated by hydrolysis rather than by transport (Ch. 11). Consequently, cholinergic neurons recover choline, rather than acetylcholine, via... 

Acetylcholine formation is limited by the intracellular concentration of choline, which is determined by active transport of choline into the nerve ending 192... 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Lips KS, Volk C, Schmitt BM, Pfeil U, Arndt P, Miska D, Ermert L, Kummer W, Koepsell FI (2005) Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am J Respir Cell Mol Biol 33 79-88. 

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).

The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine (p. 82) and serotonin (p. 116) is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, a-adrenocep-tors, and certain 5-HT and hista-mine(Hi) receptors are blocked. Interference with the dopamine system is relatively minor. 

The processes involved in neurochemical transmission in a cholinergic neuron are shown in Figure 9.2. The initial substrates for the synthesis of acetylcholine are glucose and choline. Glucose enters the neuron by means of facilitated transport. There is some disagreement as to whether choline enters cells by active or facilitated transport. Pyruvate derived from glucose is transported into mitochondria and converted to acetylcoenzyme A (acetyl-CoA). The acetyl-CoA is transported back into the cytosol. With the aid of the enzyme choline acetyl-transferase, acetylcholine is synthesized from acetyl-CoA and choline. The acetylcholine is then transported into and stored within the storage vesicles by as yet unknown mechanisms. 

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

The acetylcholine, in turn, is hydrolyzed by both acetylcholinesterase and plasma butyryl-cholinesterase. Choline is actively transported into nerve terminals (synaptosomes) by a high-affinity uptake mechanism. Furthermore, the availability of choline regulates the synthesis of acetylcholine (Figure 14.4). 

Hemicholinium blocks the transport of choline into synaptosomes, whereas botulinum toxin blocks the calcium-mediated release of acetylcholine. The released acetylcholine is hydrolyzed rapidly by acetylcholinesterase to choline and acetate. 

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