Calcium release with acetylcholine

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). 

Acetylcholine is synthesized from acetyl coenzyme A (acetyl-CoA) and choline within the presynaptic terminal by the enzyme choline acetylase. The acetylcholine formed is stored in small, lightly staining synaptic vesicles that are concentrated around the synaptic contact area. The release of acetylcholine is calcium dependent. The entire content of a synaptic vesicle is released into the cleft in an all-or-none manner, where it interacts with its receptors and then is rapidly destroyed by acetylcholinesterase. Under normal circumstances, the half-life for acetylcholine in the synaptic cleft is about 1 ms. The acetylcholine is hydrolyzed to choline and acetate, and the choline is actively pumped back into the presynaptic terminal to be used to synthesize more acetylcholine. 

Release of acetylcholine When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels in the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of acetylcholine into the synapse. This release is blocked by botulinum toxin. By contrast, black widow spider venom causes all of the cellular acetylcholine stored in synaptic vesicles to spill into the synaptic gap. 

Neuromuscular paralysis This side effect most often results after direct intraperitoneal or intrapleural application of large doses of aminoglycosides. The mechanism responsible is a decrease in both the release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site. Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or neostigmine can reverse the block. 

The aminoglycosides have a curare-like action, which can be antagonized by calcium ions and acetylcholinesterase inhibitors (8). The mechanisms include reduced release of acetylcholine prejunctionally and an interaction with the... 

DNP caused the same increase in MEPP frequency as when methylmercury was administered. However, pretreatment with 2,4-DNP did not block methylmercury-induced stimulation of MEPP frequency. Although 2,4-DNP and methylmercury were capable of individually increasing cytoplasmic calcium and stimulating spontaneous release of acetylcholine, there was no interaction between DNP and methylmercury. The authors proposed that methylmercury and DNP do not share a common mechanism for increasing cytoplasmic calcium. 

Not fully understood. Although one suggested explanation has been given nerve impulses arriving at nerve endings release calcium ions, which in turn causes the release of acetylcholine. Calcium-channel blockers can reduce the concentration of calcium ions within the nerve so that less acetylcholine is released. This would be additive with the effects of a neuromuscular blocker." ... 

Fig. 6.4 Model for protein-mediated membrane fusion and exocytosis. a The release of acetylcholine from the vesicles is mediated by a series of proteins collectively called SNARE proteins. Synaptotagmin is the neuronal Ca " receptor detecting C entry. Synaptobrevin (i.e. vesicle-associated membrane protein, VAMP) is a filament-like protein on the vesicle, b During depolarisation and calcium entry, synaptobrevin on the vesicle unfolds and forms a ternary complex with syntaxin/SNAP-25. This process is facilitated by phosphorylation of synapsin, also present on the vesicle membrane, c Assembly of the ternary complex forces the vesicle in close apposition to the nerve membrane at the active zone with release of its contents, acetylcholine. The fusion is disassembled, and the vesicle is recycled. (From Martyn 2005, p 864 copyright Elsevier)...

Magnesium is the second commonest intracellular cation, just as calcium is the second commonest extracellularly. It is the irreplaceable link that keeps ribosomes intact, and attaches mRNA to ribosomes. It is a cofactor of all the enzymes that utilize ATP in phosphate transfer, and in many other enzymes concerned with group transfer or hydrolysis. It inhibits release of acetylcholine at the motor end-plate, and in many other ways acts as a reversible antagonist to calcium. In bacteria, magnesium is the most abundant bivalent metal. The essential central atom of the chlorophyll molecule is magnesium. The higher incidence of death from heart disease in soft-water areas seems to arise from lack of Mg. ... 

A means of co-ordinating muscle contraction with glycogenolysis is required. A dramatic 100-fold increase in cytosolic Ca2+ concentration from 10 7 to 10 5 molar initiates both glycogenolysis and muscle contraction. This increase in cytosolic calcium concentration is mainly due to release of calcium from the sarcoplasmic reticulum in response to acetylcholine stimulation of the muscle fibre (Figure 7.7). 

As with all the major transmitters, acetylcholine is stored in vesicles within the nerve terminal from which it is released by a calcium-dependent mechanism following the passage of a nerve impulse. The inter-relationship between the intermediary metabolism of glucose, phospholipids and the uptake of choline is summarized in Figure 2.14. 

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.

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