PHOSPHOLIPASE-D-CATALYZED HYDROLYSIS OF PHOSPHATIDYLCHOLINE PROVIDES THE CHOLINE PRECURSOR FOR ACETYLCHOLINE SYNTHESIS IN A HUMAN NEURONAL CELL-LINE

被引:81
作者
LEE, HC
FELLENZMALONEY, MP
LISCOVITCH, M
BLUSZTAJN, JK
机构
[1] BOSTON UNIV, SCH MED, DEPT PATHOL, BOSTON, MA 02118 USA
[2] BOSTON UNIV, SCH MED, DEPT PSYCHIAT, BOSTON, MA 02118 USA
[3] WEIZMANN INST SCI, DEPT HORMONE RES, IL-76100 REHOVOT, ISRAEL
关键词
NEUROBLASTOMA; LA-N-2; CELLS; ALZHEIMER DISEASE;
D O I
10.1073/pnas.90.21.10086
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
To identify the metabolic pathway that generates choline (Cho) for acetylcholine (AcCho) from its storage pool in membrane phosphatidylcholine (PtdCho), human neuronal cells (LA-N-2) were radioisotopically labeled with 1-O-hexadecyl-2-hydroxy-sn-glyncero(3)phospho[C-14]choline. The compound was efficiently taken up by the cells and metabolically labeled PtdCho, Cho, AcCho, and phosphocholine pools. In pulse-chase experiments, the specific radioactivities of the metabolites of 1-O-hexadecyl-2-hydroxy-sn-glycero(3)phospho[C-14]choline indicated that it was rapidly acylated to PtdCho and then hydrolyzed first to free Cho and not to phosphocholine or glycerophosphocholine. This Cho was subsequently converted to AcCho and to phosphocholine. In the absence of exogenous Cho, at least 15% of the total cellular AcCho pool was synthesized by this pathway in 1 h. The data demonstrate that the liberation of the free Cho precursor for AcCho synthesis from PtdCho can be accomplished in a one-step process, indicating the involvement of a phospholipase D-type enzyme. In the presence of hemicholinium-3, which inhibits Cho transport, the amount of intracellular [C-14]Cho metabolites that accumulated during the chase period was higher than in control cells, indicating that PtdCho hydrolysis liberated Cho directly into the cytoplasm. These data show that cholinergic cells are characterized by an intracellular pathway, catalyzed by a phospholipase D, that generates Cho for AcCho synthesis from PtdCho. Abnormalities in the regulation of this pathway may contribute to selective vulnerability of cholinergic neurons in certain neurodegenerative diseases, e.g., Alzheimer disease.
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页码:10086 / 10090
页数:5
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