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October 6, 1989, Vol 262, No. 13 >
ARTICLE | October 6, 1989

Inositol Trisphosphate, Calcium, Lithium, and Cell Signaling FREE

Michael John Berridge, PhD
[+] Author Affiliations

Based on a lecture given at the presentation of the Albert Lasker Basic Medical Research Award, New York, NY, September 27, 1989.

Reprint requests to Agricultural Food Research Council Unit of Insect Neurophysiology and Pharmacology, Department of Zoology, Downing Street, Cambridge CB2 3EJ, England (Dr Berridge).


JAMA. 1989;262(13):1834-1841. doi:10.1001/jama.1989.03430130110043
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References

Inositol lipids play a major role in cell signaling by functioning as precursors of second messengers. Of the three common inositol-containing lipids found in the plasma membrane, phosphatidylinositol (4,5)-bisphosphate is hydrolyzed to give diacylglycerol, which stimulates protein kinase C, and inositol 1,4,5-trisphosphate, which diffuses into the cell to release intracellular calcium. Inositol 1,4,5-trisphosphate is metabolized to give free inositol by two separate pathways. Lithium inhibits the final dephosphorylation step of both pathways, thus reducing the supply of the free inositol required to maintain the lipid precursors used for signaling. An inositol-depletion hypothesis may explain both the teratogenic effects of lithium and its therapeutic action in controlling manic-depressive illness. One of the metabolic pathways generates inositol tetrakisphosphate, which may also play a messenger role by expanding the size of the inositol 1,4,5-trisphosphate—sensitive pool of calcium. Calcium imaging of single cells has begun to reveal that this inositol 1,4,5-trisphosphate/calcium signaling system is organized in complex patterns, which include localization of calcium signals to discrete regions of cells and the generation of both calcium waves and calcium oscillations.

(JAMA. 1989;262:1834-1841)

REFERENCES

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2 +
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3 +
Michell RH.  Inositol phospholipids and cell surface receptor function . Biochim Biophys Acta. 1975;;415:81-147.
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Prince WT, Berridge MJ.  The role of calcium in the action of 5-hydroxytryptamine and cyclic AMP on salivary glands . J Exp Biol. 1973;;58:367-384.
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Berridge MJ.  Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol . Biochem J. 1983;;212:849-858.
6 +
Streb H, Irvine RF, Berridge MJ, Schulz I.  Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4-5-trisphosphate . Nature. 1983;;306:67-69.
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Berridge MJ, Irvine RF.  Inositol trisphosphate, a novel second messenger in cellular signal transduction . Nature. 1984;;312:315-321.
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Nishizuka Y.  The role of protein kinase C in cell surface signal transduction and tumor promotion . Nature. 1984;;308:693.
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Nishizuka Y.  The molecular heterogeneity of protein kinase C and its implications for cellular regulation . Nature. 1988;;334:661-665.
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Whitman M, Downes CP, Keeler M, Keller T, Cantley L.  Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate . Nature. 1988;;332:644-646.
11 +
Stephens L, Hawkins PT, Downes CP.  Metabolic and structural evidence for the existence of a third species of polyphosphoinositide in cells: D-phosphatidyl-myo-inositol-3-phosphate . Biochem J. 1989;;259:267-276.
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Auger KR, Serunian LA, Soltoff ST, Libby P, Cantley LC.  PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells . Cell. 1989;;57:167-175.
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Berridge MJ, Fain JN.  Inhibition of phosphatidylinositol synthesis and the inactivation of calcium entry after prolonged exposure of the blowfly salivary gland to 5-hydroxytryptamine . Biochem J. 1979;;178:59-69.
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Fain JN, Berridge MJ.  Relationship between phosphatidylinositol synthesis and recovery of 5-hydroxytryptamine-responsive Ca2+ flux in blowfly salivary gland . Biochem J. 1979;;180:655-661.
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Berridge MJ, Downes CP, Hanley MR.  Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands . Biochem J. 1982;;206:587-595.
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Allison JH, Stewart MA.  Reduced brain inositol in lithium treated rats . Nature. 1971;;233:267-268.
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Berridge MJ, Dawson RMC, Downes CP, Heslop JP, Irvine RF.  Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane polyphosphoinositides . Biochem J. 1983;;212:473-482.
28 +
Michell RH, Kirk CJ, Jones LM, Downes CP, Creba JA.  The stimulation of inositol lipid breakdown that accompanies calcium mobilization in stimulated cells: defined characteristics and unanswered questions . Philos Trans R Soc Lond Biol. 1981;;296:123-137.
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Margolis RV, Press R, Altszuler N, Stewart MA.  Inositol production by the brain in normal and alloxan-diabetic dogs . Brain Res. 1971;;28:535-539.
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Barkai AI.  Myo-inositol turnover in the intact rat brain: increased production after d-amphet-amine . J Neurochem. 1981;;36:1485-1491.
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Allison HJ, Stewart MA.  Reduced brain inositol in lithium treated rats . Nature. 1971;;233:267-268.
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Godfrey PP.  Potentiation by lithium of CMP phosphatidate formation in carbachol-stimulated rat cerebral cortical slices and its reversal by myoinositol . Biochem J. 1989;;258:621-634.
34 +
Fain JN, Berridge MJ.  Relationship between phosphatidylinositol synthesis and recovery of 5-hydroxytryptamine-responsive Ca2+ flux in blowfly salivary gland . Biochem J. 1979;;180:655-661.
35 +
Monaco ME, Woods D.  Characterization of the hormone-sensitive phosphatidylinositol pool in WRK-1 cells . J Biol Chem. 1983;;258:15125-15129.
36 +
Kao KR, Masui Y, Elinson RP.  Lithium-induced respecification of pattern in Xenopus laevis embryos . Nature. 1986;;322:371-373.
37 +
Busa WB.  Roles for the phosphatidylinositol cycle in early development . Philos Trans R Soc Lond Biol. 1988;;320:415-426.
38 +
Busa WB, Gimlich RD.  Lithium-induced teratogenesis in frog embryo prevented by a polyphosphoinositide cycle intermediate or a diacylglycerol analog . Dev Biol. 1989;;132:315-324.
39 +
Berridge MJ, Downes CP, Hanley MR.  Neural and developmental actions of lithium: a unified hypothesis . Cell . In press.
40 +
Berridge MJ.  Inositol trisphosphate and diacylglycerol: two interacting second messengers . Annu Rev Biochem. 1987;;56:159-193.
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Brown KD, Blay J, Irvine RF, Heslop JP, Berridge MJ.  Reduction of epidermal growth factor receptor affinity by heterologous ligands: evidence for a mechanism involving the breakdown of phosphoinositides and the activation of protein kinase C . Biochem Biophys Res Commun. 1984;;123:377-384.
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Fein A, Payne R, Corson DW, Berridge MJ, Irvine RF.  Photoreceptor excitation and adaptation by inositol 1,4,5-trisphosphate . Nature. 1984;;311:157-160.
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Whitaker M, Irvine RF.  Inositol 1,4,5-trisphosphate microinjection activates sea urchin eggs . Nature. 1984;;312:636-639.
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Oron Y, Dascal N, Nadler E, Lupu M.  Inositol 1,4,5-trisphosphate mimics muscarinic response in Xenopus oocytes . Nature. 1985;;313:141-143.
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Berridge MJ.  Inositol trisphosphate—induced membrane potential oscillations in Xenopus oocytes . J Physiol Lond. 1988;;403:589-599.
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Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Sutherland EW, Rall TW.  Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles . J Biol Chem. 1958;;232:1077-1091.
2 +
Hokin MR, Hokin LE.  Enzyme secretion and the incorporation of P 32 into phospholipids of pancreas slices . J Biol Chem. 1953;;203:967-977.
3 +
Michell RH.  Inositol phospholipids and cell surface receptor function . Biochim Biophys Acta. 1975;;415:81-147.
4 +
Prince WT, Berridge MJ.  The role of calcium in the action of 5-hydroxytryptamine and cyclic AMP on salivary glands . J Exp Biol. 1973;;58:367-384.
5 +
Berridge MJ.  Rapid accumulation of inositol trisphosphate reveals that agonists hydrolyse polyphosphoinositides instead of phosphatidylinositol . Biochem J. 1983;;212:849-858.
6 +
Streb H, Irvine RF, Berridge MJ, Schulz I.  Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4-5-trisphosphate . Nature. 1983;;306:67-69.
7 +
Berridge MJ, Irvine RF.  Inositol trisphosphate, a novel second messenger in cellular signal transduction . Nature. 1984;;312:315-321.
8 +
Nishizuka Y.  The role of protein kinase C in cell surface signal transduction and tumor promotion . Nature. 1984;;308:693.
9 +
Nishizuka Y.  The molecular heterogeneity of protein kinase C and its implications for cellular regulation . Nature. 1988;;334:661-665.
10 +
Whitman M, Downes CP, Keeler M, Keller T, Cantley L.  Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate . Nature. 1988;;332:644-646.
11 +
Stephens L, Hawkins PT, Downes CP.  Metabolic and structural evidence for the existence of a third species of polyphosphoinositide in cells: D-phosphatidyl-myo-inositol-3-phosphate . Biochem J. 1989;;259:267-276.
12 +
Auger KR, Serunian LA, Soltoff ST, Libby P, Cantley LC.  PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells . Cell. 1989;;57:167-175.
13 +
Traynor-Kaplan AE, Harris AL, Thompson BA, Taylor P, Sklar LA.  An inositol tetrakisphosphate—containing phospholipid in activated neutrophils . Nature. 1988;;334:353-356.
14 +
Kaplan DR, Whitman M, Schaffhausen B, et al.  Common elements in growth factor stimulation and oncogenic transformation: 85kd phosphoprotein and phosphatidylinositol kinase activity . Cell. 1987;;50:1021-1029.
15 +
Coughlin SR, Escobedo JA, Williams LT.  Role of phosphatidylinositol kinase in PDGF receptor signal transductions . Science. 1989;;243:1191-1194.
16 +
Shears SB.  Metabolism of the inositol phosphates produced upon receptor activation . Biochem J. 1989;;260:313-324.
17 +
Irvine RF, Letcher AJ, Heslop JP, Berridge MJ.  The inositol tris/tetrakis phosphate pathway-demonstration of Ins(1,3,4)P3-3-kinase activity in animal tissue . Nature. 1986;;320:631-634.
18 +
Irvine RF, Moor RM, Pollock WK, Smith PM, Wreggett KA.  Inositol phosphates: proliferation, metabolism and function . Philos Trans R Soc Lond Biol. 1988;;320:281-298.
19 +
Irvine RF.  Functions of inositol phosphates . In: Michell RH, Drummond AH, Downes CP, eds. Inositol Lipids in Cell Signalling . Orlando, Fla: Academic Press Inc; 1989;:135-161.
20 +
Putney JW.  A model for receptor-regulated calcium entry . Cell Calcium. 1986;;7:1-12.
21 +
Fain JN, Berridge MJ.  Relationship between hormonal activation of phosphatidylinositol hydrolysis, fluid secretion and calcium flux in the blowfly salivary gland . Biochem J. 1979;;178:45-58.
22 +
Berridge MJ, Fain JN.  Inhibition of phosphatidylinositol synthesis and the inactivation of calcium entry after prolonged exposure of the blowfly salivary gland to 5-hydroxytryptamine . Biochem J. 1979;;178:59-69.
23 +
Fain JN, Berridge MJ.  Relationship between phosphatidylinositol synthesis and recovery of 5-hydroxytryptamine-responsive Ca2+ flux in blowfly salivary gland . Biochem J. 1979;;180:655-661.
24 +
Berridge MJ, Downes CP, Hanley MR.  Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands . Biochem J. 1982;;206:587-595.
25 +
Allison JH, Stewart MA.  Reduced brain inositol in lithium treated rats . Nature. 1971;;233:267-268.
26 +
Sherman WR.  Inositol homeostasis, lithium and diabetes . In: Michell RH, Drummond AH, Downes CP, eds. Inositol Lipids and Cell Signalling . Orlando, Fla: Academic Press Inc; 1989;:39-79.
27 +
Berridge MJ, Dawson RMC, Downes CP, Heslop JP, Irvine RF.  Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane polyphosphoinositides . Biochem J. 1983;;212:473-482.
28 +
Michell RH, Kirk CJ, Jones LM, Downes CP, Creba JA.  The stimulation of inositol lipid breakdown that accompanies calcium mobilization in stimulated cells: defined characteristics and unanswered questions . Philos Trans R Soc Lond Biol. 1981;;296:123-137.
29 +
Margolis RV, Press R, Altszuler N, Stewart MA.  Inositol production by the brain in normal and alloxan-diabetic dogs . Brain Res. 1971;;28:535-539.
30 +
Lewin LM, Yanna Y, Sulimovici S, Kraicer PF.  Studies on the metabolic role of myo-inositol: distribution of radioactive myo-inositol in the male rat . Biochem J. 1976;;156:375-380.
31 +
Barkai AI.  Myo-inositol turnover in the intact rat brain: increased production after d-amphet-amine . J Neurochem. 1981;;36:1485-1491.
32 +
Allison HJ, Stewart MA.  Reduced brain inositol in lithium treated rats . Nature. 1971;;233:267-268.
33 +
Godfrey PP.  Potentiation by lithium of CMP phosphatidate formation in carbachol-stimulated rat cerebral cortical slices and its reversal by myoinositol . Biochem J. 1989;;258:621-634.
34 +
Fain JN, Berridge MJ.  Relationship between phosphatidylinositol synthesis and recovery of 5-hydroxytryptamine-responsive Ca2+ flux in blowfly salivary gland . Biochem J. 1979;;180:655-661.
35 +
Monaco ME, Woods D.  Characterization of the hormone-sensitive phosphatidylinositol pool in WRK-1 cells . J Biol Chem. 1983;;258:15125-15129.
36 +
Kao KR, Masui Y, Elinson RP.  Lithium-induced respecification of pattern in Xenopus laevis embryos . Nature. 1986;;322:371-373.
37 +
Busa WB.  Roles for the phosphatidylinositol cycle in early development . Philos Trans R Soc Lond Biol. 1988;;320:415-426.
38 +
Busa WB, Gimlich RD.  Lithium-induced teratogenesis in frog embryo prevented by a polyphosphoinositide cycle intermediate or a diacylglycerol analog . Dev Biol. 1989;;132:315-324.
39 +
Berridge MJ, Downes CP, Hanley MR.  Neural and developmental actions of lithium: a unified hypothesis . Cell . In press.
40 +
Berridge MJ.  Inositol trisphosphate and diacylglycerol: two interacting second messengers . Annu Rev Biochem. 1987;;56:159-193.
41 +
Brown KD, Blay J, Irvine RF, Heslop JP, Berridge MJ.  Reduction of epidermal growth factor receptor affinity by heterologous ligands: evidence for a mechanism involving the breakdown of phosphoinositides and the activation of protein kinase C . Biochem Biophys Res Commun. 1984;;123:377-384.
42 +
Fein A, Payne R, Corson DW, Berridge MJ, Irvine RF.  Photoreceptor excitation and adaptation by inositol 1,4,5-trisphosphate . Nature. 1984;;311:157-160.
43 +
Whitaker M, Irvine RF.  Inositol 1,4,5-trisphosphate microinjection activates sea urchin eggs . Nature. 1984;;312:636-639.
44 +
Oron Y, Dascal N, Nadler E, Lupu M.  Inositol 1,4,5-trisphosphate mimics muscarinic response in Xenopus oocytes . Nature. 1985;;313:141-143.
45 +
Berridge MJ.  Inositol trisphosphate—induced membrane potential oscillations in Xenopus oocytes . J Physiol Lond. 1988;;403:589-599.
46 +
Busa WB, Ferguson JE, Joseph SK, Williamson JR, Nuccitelli R.  Activation of frog (Xenopus laevis) eggs by inositol trisphosphate, I: characterization of Ca2+ release from intracellular stores . J Cell Biol. 1985;;101:677-682.
47 +
Evans MG, Marty A.  Potentiation of muscarinic and α-adrenergic responses by an analogue of guanosine 5 '-trisphosphate . Proc Natl Acad Sci USA. 1986;;83:4099-4103.
48 +
Higashida H, Streaty RA, Klee W, Nirenberg M.  Bradykinin-activated transmembrane signals are coupled via No or Ni to production of inositol 1,4,5-trisphosphate, a second messenger in NG108-15 neuroblastoma-glioma hybrid cells . Proc Natl Acad Sci USA. 1986;;83:942-946.
49 +
Osugi T, Uchica S, Imaizumi T, Yoshida H.  Bradykinin-induced intracellular Ca2+ elevation in neuroblastoma × glioma hybrid NG108-15 cells: relationship to the action of inositol phospholipids metabolites . Brain Res. 1986;;379:84-89.
50 +
Mustelin T, Poso H, Andersson LC.  Role of G-proteins in T cell activation: non-hydrolyzable GTP analogues induce early ornithine decarboxylase activity in human T lymphocytes . EMBO J. 1986;;5:3287-3290.
51 +
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