Acetylcholine formation

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

The effects of non-depolarizing neuromuscular blocking drugs can be potentiated and their actions prolonged by large doses of local anesthetics, because of depression of nerve conduction, inhibition of acetylcholine formation, mobilization, and release, reduced postsynaptic receptor channel opening times, and reduced muscle contraction (370). 

DE 019 bucillamine, deacetyllanatoside C deslanoside, deanol [ban] (norcholine N-dimethylethanolamine) is isolated from a Neurospora crassa strain and is a residue present in the alkaloids cassaine and cassaidine. It is a choline precursor and has been used to enhance central acetylcholine formation. It has been used as a CNS STIMULANT (nootropic agent) to enhance mental function, and as an ANTIDEPRESSANT,... 

Several metabolic pathways (e.g. hpid metabohsm, creatine and carnitine synthesis) require methyl groups and these can be snppUed by choline or methionine. During the process of transmethylation, betaine, a tertiary amine, is formed by the oxidation of choline. Betaine can be added to the diet to act as a more direct supply of methyl groups, thus sparing choUne for its other fimctions of lecithin and acetylcholine formation, and methionine for protein synthesis. Betaine occurs in sugar beet. 

Enzyme-Catalyzed Reactions Enzymes are highly specific catalysts for biochemical reactions, with each enzyme showing a selectivity for a single reactant, or substrate. For example, acetylcholinesterase is an enzyme that catalyzes the decomposition of the neurotransmitter acetylcholine to choline and acetic acid. Many enzyme-substrate reactions follow a simple mechanism consisting of the initial formation of an enzyme-substrate complex, ES, which subsequently decomposes to form product, releasing the enzyme to react again. 

Voluntary muscle contraction is initiated in the brain-eliciting action potentials which are transmitted via motor nerves to the neuromuscular junction where acetylcholine is released causing a depolarization of the muscle cell membrane. An action potential is formed which is spread over the surface membrane and into the transverse (T) tubular system. The action potential in the T-tubular system triggers Ca " release from the sarcoplasmic reticulum (SR) into the myoplasm where Ca " binds to troponin C and activates actin. This results in crossbridge formation between actin and myosin and muscle contraction. 

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)...

Stroud, R. M., and J. Tinner-Moore, Acetylcholine receptor, structure, formation and evolution, Ann. Rev. Cell Biol., 1, 317 (1985). 

Acetylcholine is formed from acetyl CoA (produced as a byproduct of the citric acid and glycolytic pathways) and choline (component of membrane lipids) by the enzyme choline acetyltransferase (ChAT). Following release it is degraded in the extracellular space by the enzyme acetylcholinesterase (AChE) to acetate and choline. The formation of acetylcholine is limited by the intracellular concentration of choline, which is determined by the (re)uptake of choline into the nerve ending (Taylor Brown, 1994). 

Vazquez, J. Baghdoyan, H. A. (2004). GABAA receptors inhibit acetylcholine release in cat pontine reticular formation implications for REM sleep regulation. J. Neurophysiol. 92, 2198-206. 

Baghdoyan, H. A., Lydic, R. Fleegal, M. A. (1998). M2 muscarinic autoreceptors modulate acetylcholine release in the medial pontine reticular formation. 

Coleman, C. G., Baghdoyan, H. A. 8r Lydic, R. (2006). Dialysis delivery of an adenosine A2A agonist into the pontine reticular formation of C57BL/6J mouse increases pontine acetylcholine release and sleep. J. Neurochem. 96, 1750-9. 

Lydic, R., Keifer, J. C., Baghdoyan, H. A. Becker, L. (1993). Microdialysis of the pontine reticular formation reveals inhibition of acetylcholine release by morphine. Anesthesiology 79, 1003-12. 

The neural structures involved in the promotion of the waking (W) state are located in the (1) brainstem [dorsal raphe nucleus (DRN), median raphe nucleus (MRN), locus coeruleus (LC), laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), and medial-pontine reticular formation (mPRF)] (2) hypothalamus [tuberomammillary nucleus (TMN) and lateral hypothalamus (LH)[ (3) basal forebrain (BFB) (medial septal area, nucleus basalis of Meynert) and (4) midbrain ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) (Pace-Schott Hobson, 2002 Jones, 2003). The following neurotransmitters function to promote W (1) acetylcholine (ACh LDT/PPT, BFB) (2) noradrenaline (NA LC) (3) serotonin (5-HT DRN, MRN) (4) histamine (HA TMN) (5) glutamate (GLU mPRF, BFB, thalamus) (6) orexin (OX LH) and (7) dopamine (DA VTA, SNc) (Zoltoski et al, 1999 Monti, 2004). 

Incorporation of fluorine at a site adjacent to a "metabolic soft spot" has also been used as a strategy to increase duration of action. Linopir-dine (24) was among the first clinical compounds that enhanced potassium-evoked release of acetylcholine in preclinical models of AD [22]. Linopirdine showed no clinical efficacy and its human pharmacokinetic profile was suggested as the reason for this lack of clinical efficacy. Specifically noted was the molecule s poor brain exposure and short half-life due to formation of the N-oxides 25 and 26 (Table 3) [23,24]. Optimization of 24 resulted in replacement of the indolone core by the anthracenone 27, which had improved in vitro activity, but still exhibited a short duration of action. To improve the metabolic stability, fluorine... 

Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse. For instance, the acetylcholine receptor (AChR) is concentrated at the postsynaptic membrane of the neuromuscular junction at a density of 10,000 receptors/pm2, which is about three orders of magnitude higher than that of the extrasynaptic region... 

Kar S, Seto D, Dore S, Hanisch U-K, Quirion R. 1997a. Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation. Proc Natl Acad Sci USA 94 14054-14059. 

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