Choline-transporter

Geldenhuys WJ, Lockman PR, McAfee JH, Fitzpatrick KT, Van der Schyf CJ and Allen DD. Molecular modeling studies on the active binding site of the blood-brain barrier choline transporter. Bioorg Med Chem Lett 2004 14 3085-92. 

Two additional permeases from Saccharomyces cerevisiae share lower homologies with this family of transporters. One of them is the UGA4 GABA-specific permease ([49], Fig. 2 and Andre, Hein, Grenson and Jauniaux, submitted) the second is the CTR choline transporter [50]. About 19% of the amino acid residues of these two proteins are identical. They show about 10% identity with each of the six amino acid permeases mentioned above. This identity does not include most of the amino acids which are highly conserved among the six permeases. 

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,... 

Ferguson, S. M., Savchenko V., Apparsundaram, S. etal. Vesicular localization and activity-dependent trafficking of presynaptic choline transporters. J. Neurosci. 23 9697-9709,... 

The biosynthesis and storage of ACh can be divided into three processes that allow for recovery of hydrolyzed transmitter by choline transport back into the nerve ending, conversion by acetylation to active transmitter and then storage in a vesicle for subsequent release [16-21] (Fig. 11-4). 

Okuda, T., Haga, T., Kanai, Y., Endou, H., Ishihara, T. and Katsura, I. Identification and characterization of the high affinity choline transporter. Nat. Neurosci. 3,120-125,2000. 

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],... 

Transport back into the noradrenergic neuron (reup-take), followed by either vesicular storage or by enzymatic inactivation by mitochondrial MAO. The transport of norepinephrine into the neurons is a sodium-facilitated process similar to that for choline transport. 

R. Katz-Brull, H. Degani, Kinetics of choline transport and phosphorylation in human breast cancer cells NMR application of the zero trans method. Anticancer Res. 16 (3B) (1996) 1375-1380. 

Lee G, lingsch C, Lyle PT, et al Lithium treatment strongly inhibits choline transport in human erythrocytes. Br J Chn Pharmacol 1 365-370, 1974 Lee KF, li E, Huber J, et al Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral nervous system. Cell 69 737-749, 1992... 

Uney JB, Marchbanks RM, Marsh A The effect of lithium on choline transport in human erythrocytes. J Neurol Neurosurg Psychiatry 48 229-233, 1985... 

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.

Martin, K.A.C. (1971). Some properties of an SH group essential for choline transport in human erythrocytes. J. Physiol. Lond. 213,647-664. 

Allen, D.D., and P.R. Lockman. 2003. The blood-brain barrier choline transporter as a brain drug delivery vector. Life Sci 73 1609. 

Ferguson SM, Blakely RD (2004) The choline transporter resurfaces new roles for synaptic vesicles Mol Interv 4 22-37. 

Matthies DS, Fleming PA, Wilkes DM, Blakely RD (2006) The Caenorhabditis elegans choline transporter CHO-1 sustains acetylcholine synthesis and motor function in an activity-dependent manner. J Neurosci 26 6200-6212. 

Acethylcholine synthesis and release In the presynaptic cholinergic terminal. Ach, acetylcholine ChAT, choline acetyltransferase VAChT, vesicular acetylcholine transporter AChE, acetylcholineesterase CHT, choline transporter... 

Bazalakova MH, Blakely RD. 2006. The high-affinity choline transporter A critical protein for sustaining cholinergic signaling as revealed in studies of genetically altered mice. Handb Exp Pharmacol 175 525-544. 

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