Choline transport mechanism

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

The second phase of phospholipid synthesis in eukaryotes. Choline or ethanolamine enters the cell via active transport mechanisms and is immediately phosphorylated by the enzyme, choline (ethanolamine) kinase. The phosphorylated derivatives of choline and ethanolamine... 

Choline is accumulated in cholinergic presynaptic nerve endings via an active transport mechanism linked to a Na+ pump. 

Choline is not made de novo in animal cells except by the methylation of PE to PC and subsequent hydrolysis of the choline moiety from PC. Therefore, choline is imported from extracellular sources. Choline is an important nutrient in the diet of animals and is required in the medium of animal cells in culture (H. Eagle, 1955). Choline is essential because of the cell s requirement for PC for growth and division. There are two distinct transport mechanisms for entry of choline into cells [5] a high affinity K or AT, < 5 pM), Na" -dependent transporter and a lower affinity K > 30 pM), Na -independent transporter. Several cDNAs encoding proteins that show high affinity transport of choline have been reported. 

The synthesis of acetylcholine from acetyl CoA and choline is catalyzed by the enzyme choline acetyltransferase (ChAT) (Fig. 48.9). This synthetic step occurs in the presynaptic terminal. The compound is stored in vesicles and later released through calcium-mediated exocytosis. Choline is taken up by the presynaptic terminal from the blood via a low-affinity transport system (high and from the synaptic cleft via a high-affmity transport mechanism (low K. It is also derived from the hydrolysis of phosphatidylcholine (and possibly sphingomyelin) in membrane lipids. Thus, membrane lipids may form a storage site for choline, and their hydrolysis, with the subsequent release of choline, is highly regulated. 

In the present paper we describe the results of our studies on the biosynthesis and turnover of phosphatidyl choline (PC) in rat brain. We will discuss the apparent lack of phospholipid transport mechanisms in cell membranes of the CNS and will show that all brain subcellular fractions seem to have a certain degree of independence for the synthesis of this phospholipid. The presence of rapid and slow turnover pools for PC will be described and possible explanations for these findings will be presented. 

Choline, an amino alcohol, is the precursor of phospholipids, which are ubiquitous components of cell membranes. Choline can be labeled with "C (50) or F (51,52) and is taken up by tumor cells via an active transport mechanism. It is subsequently trapped through phosphorylation by choline kinase to... 

Studies on the neurochemical effects of Pb on the cholinergic system have assessed the effects in terms of (1) steady-state levels of ACh and its precursor choline (Ch), (2) cholinergic eniymes, (3) rate of ACh release and turnover, (4) synaptosomal transport mechanisms, and (5) pharmacological responses of Pb-exposed animals. 

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. 

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... 

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). 

As explained previously, electrodissolution in ionic liquids is a simple and efficient process, particularly in chloride-based eutectics. Type III eutectics based on hydrogen bond donors are particularly suitable for this purpose. However, it has been noted that the polishing process only occurs in very specific liquids and even structurally related compounds are often not effective. It has been shown that 316 series stainless steels can be electropolished in choline chloride ethylene glycol eutectics [19] and extensive electrochemical studies have been carried out. The dissolution process in aqueous solutions has been described by two main models the duplex salt model, which describes a compact and porous layer at the iron surface [20], and an adsorbate-acceptor mechanism, which looks at the role of adsorbed metallic species and the transport of the acceptor which solubilises... 

Mechanism of action Mechlorethamine is transported into the cell by a choline uptake process. The drug loses a chloride ion and forms a reactive intermediate that alkylates the N7 nitrogen of a... 

Membrane phospholipids are synthesized on the cytoplasmic side of SER membrane. Because the polar head groups of phospholipid molecules make transport across the hydrophobic core of a membrane an unlikely event, a translocation mechanism is used to transfer phospholipids across the membrane to ensure balanced growth. Choline-containing phospholipids are found in high concentration on the lumenal side of ER membrane because a prominent phospholipid translocator protein called flippase preferentially transfers this class of molecule. 

Whereas acetylcholine is degraded by a membrane-anchored acetylcholine esterase (ACE) in the synaptic cleft (choline is afterwards taken up presynaptically), the biogenic amines adrenaline, noradrenaline, serotonin, and dopamine are taken up by the presynaptic membrane by transporters (Fig. 3) or by extraneuronal cells in which they are degraded by a catecholamine O-methyltransferase (COMT). These transporter have similar structure and contain 12 transmembrane regions. Once in the presynapse, the neurotransmitters are either degraded by monoamine oxidase (MAO) or taken up by synaptic vesicles. A proton pumping ATPase of the vesicle membrane (V-type ATPase as in plant vacuoles) causes an increase of hydrogen ion concentrations in the vesicles. Uptake of the neurotransmitter serotonin, adrenaline and noradrenaline could be partly achieved either via a diffusion of the free base into the vesicles where they become protonated and concentrated by an "ion trap" mechanism and via specific proton-coupled antiporters. The excitatory amino acids, acetylcholine and ATP cannot diffuse and enter the vesicles via specific transporters. 

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