REDUCED INOSITOL POLYPHOSPHATE ACCUMULATION AND INOSITOL SUPPLY INDUCED BY LITHIUM IN STIMULATED CEREBRAL-CORTEX SLICES

被引:103
作者
KENNEDY, ED
CHALLISS, RAJ
RAGAN, CI
NAHORSKI, SR
机构
[1] UNIV LEICESTER,DEPT PHARMACOL & THERAPEUT,POB 138,MED SCI BLDG,UNIV RD,LEICESTER LE1 9HN,ENGLAND
[2] MERCK SHARP & DOHME LTD,NEUROSCI RES CTR,HARLOW CM20 2QR,ESSEX,ENGLAND
基金
英国惠康基金;
关键词
D O I
10.1042/bj2670781
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The ability of lithium to interfere with phosphoinositide metabolism in rat cerebral cortex slices has been examined by monitoring the accumulation of CMP-phosphatidate (CMP-PtdOH) and the reduction in Ins(1,4,5)P3 and Ins(1,3,4,5)P4 levels. A small accumulation of [14C]CMP-PtdOH was seen in slices prelabelled with [14C]cytidine and stimulated with carbachol (1 mM) or Li+ (1 mM). However, simultaneous addition of both agents for 30 min produced a 22-fold accumulation, with Li+ producing a half-maximal effect at a concentration of 0.61 ± 0.19 mM. Kinetic studies revealed that the effects of carbachol and Li+ on CMP-PtdOH accumulation occurred with no initial lag apparent under these conditions and that preincubation with myo-inositol (10 or 30 mM) dramatically attenuated CMP-PtdOH accumulation. myo-Inositol could also attenuate the rate of accumulation of CMP-PtdOH when added 20 min after carbachol and Li+; these effects were not observed when equimolar concentrations of scyllo-inositol were added. Use of specific radioreceptor assays allowed the mass accumulations of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 to be monitored. Following a lag of 5-10 min, Li+ resulted in a marked reduction in the accumulation of both inositol polyphosphates resulting from muscarinic-cholinergic stimulation. Preincubation of cerebral cortex slices with myo- (but not scyllo-) inositol delayed, but did not prevent, the reduction in the accumulation of Ins(1,4,5)P3 or Ins(1,3,4,5)P4. The results suggest that cerebral cortex, at least in vitro, is very sensitive to myo-inositol depletion under conditions of muscarinic receptor stimulation. The relationship of such depletion to the generation of inositol polyphosphate second messengers is discussed.
引用
收藏
页码:781 / 786
页数:6
相关论文
共 33 条
[1]   REDUCED BRAIN INOSITOL IN LITHIUM-TREATED RATS [J].
ALLISON, JH ;
STEWART, MA .
NATURE-NEW BIOLOGY, 1971, 233 (43) :267-&
[2]  
BALLA T, 1988, J BIOL CHEM, V263, P4083
[3]   DIFFERENTIAL-EFFECTS OF LITHIUM ON MUSCARINIC RECEPTOR STIMULATION OF INOSITOL PHOSPHATES IN RAT CEREBRAL-CORTEX SLICES [J].
BATTY, I ;
NAHORSKI, SR .
JOURNAL OF NEUROCHEMISTRY, 1985, 45 (05) :1514-1521
[4]   RAPID ACCUMULATION AND SUSTAINED TURNOVER OF INOSITOL PHOSPHATES IN CEREBRAL-CORTEX SLICES AFTER MUSCARINIC-RECEPTOR STIMULATION [J].
BATTY, IH ;
NAHORSKI, SR .
BIOCHEMICAL JOURNAL, 1989, 260 (01) :237-241
[5]   ACCUMULATION OF INOSITOL POLYPHOSPHATE ISOMERS IN AGONIST-STIMULATED CEREBRAL-CORTEX SLICES - COMPARISON WITH METABOLIC PROFILES IN CELL-FREE PREPARATIONS [J].
BATTY, IH ;
LETCHER, AJ ;
NAHORSKI, SR .
BIOCHEMICAL JOURNAL, 1989, 258 (01) :23-32
[6]  
BATTY IH, 1987, BIOCHEM J, V247, P707
[7]   NEURAL AND DEVELOPMENTAL ACTIONS OF LITHIUM - A UNIFYING HYPOTHESIS [J].
BERRIDGE, MJ ;
DOWNES, CP ;
HANLEY, MR .
CELL, 1989, 59 (03) :411-419
[8]   LITHIUM AMPLIFIES AGONIST-DEPENDENT PHOSPHATIDYLINOSITOL RESPONSES IN BRAIN AND SALIVARY-GLANDS [J].
BERRIDGE, MJ ;
DOWNES, CP ;
HANLEY, MR .
BIOCHEMICAL JOURNAL, 1982, 206 (03) :587-595
[9]   LITHIUM-INDUCED TERATOGENESIS IN FROG EMBRYOS PREVENTED BY A POLYPHOSPHOINOSITIDE CYCLE INTERMEDIATE OR A DIACYLGLYCEROL ANALOG [J].
BUSA, WB ;
GIMLICH, RL .
DEVELOPMENTAL BIOLOGY, 1989, 132 (02) :315-324
[10]   MASS MEASUREMENTS OF INOSITOL(1,4,5)TRISPHOSPHATE IN RAT CEREBRAL-CORTEX SLICES USING A RADIORECEPTOR ASSAY - EFFECTS OF NEUROTRANSMITTERS AND DEPOLARIZATION [J].
CHALLISS, RAJ ;
BATTY, IH ;
NAHORSKI, SR .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1988, 157 (02) :684-691