Regulation of Acetylcholine Synthesis in the Brain

Tuček, Stanislav

doi:10.1111/j.1471-4159.1985.tb07106.x

Cited by 264 publications

(97 citation statements)

References 159 publications

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“…Its activity is based on the competitive inhibition of the high a nity, Na + -and Cl 7 -dependent choline transport system (Guyenet et al, 1973;Polak et al, 1977;Zlatkine et al, 1993). HC-3 has a much less inhibitory e ect on the low-a nity sodium independent choline transport system, which is related to the biosynthetic pathway converting choline into phosphatidylcholine in all cell types (Tucek, 1985). However, HC-3 also a ects the biosynthesis of phosphorylcholine (PCho) by competitive inhibition of ChoK.…”

Section: Discussionmentioning

confidence: 99%

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Saniger²,

et al. 1997

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Recent progress in deciphering the molecular basis of carcinogenesis is of utmost importance to the development of new anticancer strategies. To this end, it is essential to understand the regulation of both normal cell proliferation and its alterations in cancer cells. We have previously demonstrated that in ras-transformed cells there is an increased level of phosphorylcholine (PCho) resulting from a constitutive activation on choiline kinase (ChoK). The importance of ChoK for the regulation of cell proliferation has also been proposed since an inhibitor for this enzyme, hemicholinium-3 (HC-3), drastically reduces entry into the S phase after stimulation with growth factors. Here we report the synthesis of several new compounds which are highly speci®c inhibitors for ChoK, with up to 1000-fold or 600-fold increased inhibitory activity, compared to HC-3 under ex vivo or in vitro conditions respectively. These novel compounds also drastically reduce entry into the S phase after stimulation with speci®c growth factors. A more profound inhibition of cell proliferation was observed in ras-, src-and mos-transformed cells in the presence of ChoK inhibitors, compared to their parental, untransformed NIH3T3 cells. By contrast, this e ect was not observed in fos-transformed cells. While ras, src and mos transformation is associated with elevated levels of ChoK activity, fos-induced transformation does not a ect ChoK activity. The inhibitory e ect on proliferation of the new compounds correlates with their ability to inhibit the production of phosphorylcholine in whole cells, a proposed novel second messenger for cell proliferation. These results strongly support a critical role of choline kinase in the regulation of cell growth and makes this enzyme a novel target for the design of new antiproliferative and anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Saniger²,

et al. 1997

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“…ChAT (EC 2.3.1.6) catalyses the conversion of choline to ACh, and although kinetic considerations show its activity to be at a high enough level to preclude a direct regulatory role in ACh synthesis (37), it is considered to be a key element and a specific marker of cholinergic neurons. Smallman and Pal (56) first demonstrated the very high specific activity of ChAT in the nervous system of the cockroach Periplaneta americana.…”

Section: Enzymology Of Chatmentioning

confidence: 99%

“…An essential prerequisite for the function of cholinergic synapses is the availability of exogenous choline, which is accumulated via specific, high-affinity, choline carrier molecules in the presynaptic terminal membrane and converted to ACh in the nerve terminal cytoplasm (37). The high-affinity uptake of choline appears to be unique for cholinergic nerve endings and is not present in perikarya (38).…”

Section: Kineticsmentioning

confidence: 99%

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Sattelle

Breert

1990

J Neuroendocrinology

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“…THE MAJORITY OF CHOLINE is incorporated into phosphatidylcholine (PC) or proceeds through mitochondrial oxidation to betaine, thus entering the one-carbon methylation pool (74,62), or is used in the production of the neurotransmitter acetylcholine (45). Interest in the factors that influence choline transport and metabolism has grown because of choline's association with neural tube defects (49,51), memory development (75), Alzheimer's disease (53), homocysteine production (50), and inherited disorders of neuromuscular transmission (40,78).…”

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confidence: 99%

Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1

Yuan

Tie

Tarnopolsky

et al. 2006

Physiological Genomics

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line transporter-like (CTL) proteins of the CTL1 family are novel transmembrane proteins implicated in choline transport for phospholipid synthesis. In this study, we characterized the 5Ј-flanking region of the human (h)CTL1 gene and examined some of the possible mechanisms of its regulation, including promoter activity, splicing, and expression. The transcription start site of the hCTL1 gene was mapped by 5Ј-rapid amplification of cDNA ends (RACE), and the presence of two splice variants, hCTL1a and hCTL1b, was investigated using isoform-specific PCR and 3Ј-RACE. The hCTL1 promoter region of ϳ900 bp was isolated from MCF-7 human breast cancer cells. The promoter was TATA-less and driven by a long stretch of GC-rich sequence in accordance with widespread expression of hCTL1 at both mRNA and protein levels. Deletion analyses demonstrated that a very strong promoter is contained within 500 bp of the transcription start site, and more upstream regions did not increase its activity. The core promoter that conferred the minimal transcription is within the Ϫ188/ϩ27-bp region, and its activity varied in human breast cancer and mouse skeletal muscle cells. Multiple motifs within the promoter regulatory region bound nuclear factors from both cultured cells and normal human skeletal muscle. The motifs within the three regions [S1 (Ϫ92/Ϫ61 bp), S2 (Ϫ174/Ϫ145 bp), and S3 (Ϫ289/Ϫ260 bp)] contained overlapping binding sites for hematopoietic transcription factors and ubiquitous transcription factors, in line with the expected gene function. Genomic analyses demonstrated a high conservation of hCTL1 and mouse CTL1 proximal promoters. Accordingly, mRNA profiles demonstrated that human splice variants were expressed ubiquitously, as demonstrated for the mouse transcripts; however, they differed from the profiles of rat CTL1 transcripts, which were more restricted to neurons and intestinal tissues. The shorter hCTL1b variant contained the cytosolic COOH-terminal motif L 651 KKR 654 for endoplasmic reticulum retrieval/retention. This retention signal was conserved in hCTL1b and rat and mouse CTL1b and is typical for transmembrane proteins of type 1 topology.choline transporter-like protein 1 promoters; gene expression THE MAJORITY OF CHOLINE is incorporated into phosphatidylcholine (PC) or proceeds through mitochondrial oxidation to betaine, thus entering the one-carbon methylation pool (74, 62), or is used in the production of the neurotransmitter acetylcholine (45). Interest in the factors that influence choline transport and metabolism has grown because of choline's association with neural tube defects (49, 51), memory development (75), Alzheimer's disease (53), homocysteine production (50), and inherited disorders of neuromuscular transmission (40, 78). The phosphorylation of intracellular choline by choline kinase and the subsequent production of CDP-choline, the main precursor of PC, by CTP:phosphocholine cytidylytransferase (Pcyt1) are the principal pathways for choline utilization and have been extensively studied and are ...

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Regulation of Acetylcholine Synthesis in the Brain

Cited by 264 publications

References 159 publications

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Choline kinase inhibitors as a novel approach for antiproliferative drug design

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1

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