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. 1997 Apr 15;16(8):1943–1952. doi: 10.1093/emboj/16.8.1943

D-myo-inositol 1,4,5-trisphosphate 3-kinase A is activated by receptor activation through a calcium:calmodulin-dependent protein kinase II phosphorylation mechanism.

D Communi 1, V Vanweyenberg 1, C Erneux 1
PMCID: PMC1169797  PMID: 9155020

Abstract

D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] 3-kinase, the enzyme responsible for production of D-myo-inositol 1,3,4,5-tetrakisphosphate, was activated 3- to 5-fold in homogenates of rat brain cortical slices after incubation with carbachol. The effect was reproduced in response to UTP in Chinese hamster ovary (CHO) cells overexpressing Ins(1,4,5)P3 3-kinase A, the major isoform present in rat and human neuronal cells. In ortho-32P-labelled cells, the phosphorylated 53 kDa enzyme could be identified after receptor activation by immunoprecipitation. The time course of phosphorylation was very similar to that observed for carbachol (or UTP)-induced enzyme activation. Enzyme phosphorylation was prevented in the presence of okadaic acid. Calmodulin (CaM) kinase II inhibitors (i.e. KN-93 and KN-62) prevented phosphorylation of Ins(1,4,5)P3 3-kinase. Identification of the phosphorylation site in transfected CHO cells indicated that the phosphorylated residue was Thr311. This residue of the human brain sequence lies in an active site peptide segment corresponding to a CaM kinase II-mediated phosphorylation consensus site, i.e. Arg-Ala-Val-Thr. The same residue in Ins(1,4,5)P3 3-kinase A was also phosphorylated in vitro by CaM kinase II. Phosphorylation resulted in 8- to 10-fold enzyme activation and a 25-fold increase in sensitivity to the Ca2+:CaM complex. In this study, direct evidence is provided for a novel regulation mechanism for Ins(1,4,5)P3 3-kinase (isoform A) in vitro and in intact cells.

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Selected References

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  1. Baba H., Fuss B., Urano J., Poullet P., Watson J. B., Tamanoi F., Macklin W. B. GapIII, a new brain-enriched member of the GTPase-activating protein family. J Neurosci Res. 1995 Aug 15;41(6):846–858. doi: 10.1002/jnr.490410615. [DOI] [PubMed] [Google Scholar]
  2. Batty I. R., Nahorski S. R., Irvine R. F. Rapid formation of inositol 1,3,4,5-tetrakisphosphate following muscarinic receptor stimulation of rat cerebral cortical slices. Biochem J. 1985 Nov 15;232(1):211–215. doi: 10.1042/bj2320211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beltman J., Sonnenburg W. K., Beavo J. A. The role of protein phosphorylation in the regulation of cyclic nucleotide phosphodiesterases. Mol Cell Biochem. 1993 Nov;127-128:239–253. doi: 10.1007/BF01076775. [DOI] [PubMed] [Google Scholar]
  4. Berridge M. J. Inositol trisphosphate and calcium signalling. Nature. 1993 Jan 28;361(6410):315–325. doi: 10.1038/361315a0. [DOI] [PubMed] [Google Scholar]
  5. Biden T. J., Altin J. G., Karjalainen A., Bygrave F. L. Stimulation of hepatic inositol 1,4,5-trisphosphate kinase activity by Ca2+-dependent and -independent mechanisms. Biochem J. 1988 Dec 15;256(3):697–701. doi: 10.1042/bj2560697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burns F., Zhao A. Z., Beavo J. A. Cyclic nucleotide phosphodiesterases: gene complexity, regulation by phosphorylation, and physiological implications. Adv Pharmacol. 1996;36:29–48. doi: 10.1016/s1054-3589(08)60575-x. [DOI] [PubMed] [Google Scholar]
  7. Challiss R. A., Nahorski S. R. Neurotransmitter and depolarization-stimulated accumulation of inositol 1,3,4,5-tetrakisphosphate mass in rat cerebral cortex slices. J Neurochem. 1990 Jun;54(6):2138–2141. doi: 10.1111/j.1471-4159.1990.tb04920.x. [DOI] [PubMed] [Google Scholar]
  8. Changya L., Gallacher D. V., Irvine R. F., Potter B. V., Petersen O. H. Inositol 1,3,4,5-tetrakisphosphate is essential for sustained activation of the Ca2+-dependent K+ current in single internally perfused mouse lacrimal acinar cells. J Membr Biol. 1989 Jul;109(1):85–93. doi: 10.1007/BF01870793. [DOI] [PubMed] [Google Scholar]
  9. Choi K. Y., Kim H. K., Lee S. Y., Moon K. H., Sim S. S., Kim J. W., Chung H. K., Rhee S. G. Molecular cloning and expression of a complementary DNA for inositol 1,4,5-trisphosphate 3-kinase. Science. 1990 Apr 6;248(4951):64–66. doi: 10.1126/science.2157285. [DOI] [PubMed] [Google Scholar]
  10. Communi D., Lecocq R., Erneux C. Arginine 343 and 350 are two active residues involved in substrate binding by human Type I D-myo-inositol 1,4,5,-trisphosphate 5-phosphatase. J Biol Chem. 1996 May 17;271(20):11676–11683. doi: 10.1074/jbc.271.20.11676. [DOI] [PubMed] [Google Scholar]
  11. Communi D., Lecocq R., Vanweyenberg V., Erneux C. Active site labelling of inositol 1,4,5-trisphosphate 3-kinase A by phenylglyoxal. Biochem J. 1995 Aug 15;310(Pt 1):109–115. doi: 10.1042/bj3100109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hanson P. I., Meyer T., Stryer L., Schulman H. Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron. 1994 May;12(5):943–956. doi: 10.1016/0896-6273(94)90306-9. [DOI] [PubMed] [Google Scholar]
  13. Human G. P., Dormehl I. Die diagnose van isgemiese hartsiekte met tallium-201. S Afr Med J. 1981 Apr 4;59(15):529–532. [PubMed] [Google Scholar]
  14. Irvine R. F., Moor R. M., Pollock W. K., Smith P. M., Wreggett K. A. Inositol phosphates: proliferation, metabolism and function. Philos Trans R Soc Lond B Biol Sci. 1988 Jul 26;320(1199):281–298. doi: 10.1098/rstb.1988.0077. [DOI] [PubMed] [Google Scholar]
  15. Ismailov I. I., Fuller C. M., Berdiev B. K., Shlyonsky V. G., Benos D. J., Barrett K. E. A biologic function for an "orphan" messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10505–10509. doi: 10.1073/pnas.93.19.10505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ito I., Hidaka H., Sugiyama H. Effects of KN-62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, on long-term potentiation in the rat hippocampus. Neurosci Lett. 1991 Jan 2;121(1-2):119–121. doi: 10.1016/0304-3940(91)90663-e. [DOI] [PubMed] [Google Scholar]
  17. Johnson R. M., Wasilenko W. J., Mattingly R. R., Weber M. J., Garrison J. C. Fibroblasts transformed with v-src show enhanced formation of an inositol tetrakisphosphate. Science. 1989 Oct 6;246(4926):121–124. doi: 10.1126/science.2506643. [DOI] [PubMed] [Google Scholar]
  18. Lee S. Y., Sim S. S., Kim J. W., Moon K. H., Kim J. H., Rhee S. G. Purification and properties of D-myo-inositol 1,4,5-trisphosphate 3-kinase from rat brain. Susceptibility to calpain. J Biol Chem. 1990 Jun 5;265(16):9434–9440. [PubMed] [Google Scholar]
  19. Loomis-Husselbee J. W., Cullen P. J., Dreikausen U. E., Irvine R. F., Dawson A. P. Synergistic effects of inositol 1,3,4,5-tetrakisphosphate on inositol 2,4,5-triphosphate-stimulated Ca2+ release do not involve direct interaction of inositol 1,3,4,5-tetrakisphosphate with inositol triphosphate-binding sites. Biochem J. 1996 Mar 15;314(Pt 3):811–816. doi: 10.1042/bj3140811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mailleux P., Takazawa K., Albala N., Erneux C., Vanderhaeghen J. J. Comparison of neuronal inositol 1,4,5-trisphosphate 3-kinase and receptor mRNA distributions in the human brain using in situ hybridization histochemistry. Neurosci Lett. 1992 Mar 16;137(1):69–71. doi: 10.1016/0304-3940(92)90300-v. [DOI] [PubMed] [Google Scholar]
  21. Mailleux P., Takazawa K., Erneux C., Vanderhaeghen J. J. Inositol 1,4,5-trisphosphate 3-kinase distribution in the rat brain. High levels in the hippocampal CA1 pyramidal and cerebellar Purkinje cells suggest its involvement in some memory processes. Brain Res. 1991 Jan 25;539(2):203–210. doi: 10.1016/0006-8993(91)91622-8. [DOI] [PubMed] [Google Scholar]
  22. Schulman H., Hanson P. I., Meyer T. Decoding calcium signals by multifunctional CaM kinase. Cell Calcium. 1992 Jun-Jul;13(6-7):401–411. doi: 10.1016/0143-4160(92)90053-u. [DOI] [PubMed] [Google Scholar]
  23. Sim S. S., Kim J. W., Rhee S. G. Regulation of D-myo-inositol 1,4,5-trisphosphate 3-kinase by cAMP-dependent protein kinase and protein kinase C. J Biol Chem. 1990 Jun 25;265(18):10367–10372. [PubMed] [Google Scholar]
  24. Takazawa K., Lemos M., Delvaux A., Lejeune C., Dumont J. E., Erneux C. Rat brain inositol 1,4,5-trisphosphate 3-kinase. Ca2(+)-sensitivity, purification and antibody production. Biochem J. 1990 May 15;268(1):213–217. doi: 10.1042/bj2680213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Takazawa K., Perret J., Dumont J. E., Erneux C. Molecular cloning and expression of a new putative inositol 1,4,5-trisphosphate 3-kinase isoenzyme. Biochem J. 1991 Sep 15;278(Pt 3):883–886. doi: 10.1042/bj2780883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Thomas S., Brake B., Luzio J. P., Stanley K., Banting G. Isolation and sequence of a full length cDNA encoding a novel rat inositol 1,4,5-trisphosphate 3-kinase. Biochim Biophys Acta. 1994 Jan 13;1220(2):219–222. doi: 10.1016/0167-4889(94)90139-2. [DOI] [PubMed] [Google Scholar]
  27. Trimble E. R., Bruzzone R., Meehan C. J., Biden T. J. Rapid increases in inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and cytosolic free Ca2+ in agonist-stimulated pancreatic acini of the rat. Effect of carbachol, caerulein and secretin. Biochem J. 1987 Feb 15;242(1):289–292. doi: 10.1042/bj2420289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tsubokawa H., Oguro K., Robinson H. P., Masuzawa T., Rhee T. S., Takenawa T., Kawai N. Inositol 1,3,4,5-tetrakisphosphate as a mediator of neuronal death in ischemic hippocampus. Neuroscience. 1994 Mar;59(2):291–297. doi: 10.1016/0306-4522(94)90597-5. [DOI] [PubMed] [Google Scholar]
  29. Vajanaphanich M., Schultz C., Rudolf M. T., Wasserman M., Enyedi P., Craxton A., Shears S. B., Tsien R. Y., Barrett K. E., Traynor-Kaplan A. Long-term uncoupling of chloride secretion from intracellular calcium levels by Ins(3,4,5,6)P4. Nature. 1994 Oct 20;371(6499):711–714. doi: 10.1038/371711a0. [DOI] [PubMed] [Google Scholar]
  30. Vanweyenberg V., Communi D., D'Santos C. S., Erneux C. Tissue- and cell-specific expression of Ins(1,4,5)P3 3-kinase isoenzymes. Biochem J. 1995 Mar 1;306(Pt 2):429–435. doi: 10.1042/bj3060429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Yamaguchi K., Hirata M., Kuriyama H. Calmodulin activates inositol 1,4,5-trisphosphate 3-kinase activity in pig aortic smooth muscle. Biochem J. 1987 Jun 15;244(3):787–791. doi: 10.1042/bj2440787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yan C., Zhao A. Z., Bentley J. K., Beavo J. A. The calmodulin-dependent phosphodiesterase gene PDE1C encodes several functionally different splice variants in a tissue-specific manner. J Biol Chem. 1996 Oct 11;271(41):25699–25706. doi: 10.1074/jbc.271.41.25699. [DOI] [PubMed] [Google Scholar]
  33. Zilberman Y., Howe L. R., Moore J. P., Hesketh T. R., Metcalfe J. C. Calcium regulates inositol 1,3,4,5-tetrakisphosphate production in lysed thymocytes and in intact cells stimulated with concanavalin A. EMBO J. 1987 Apr;6(4):957–962. doi: 10.1002/j.1460-2075.1987.tb04845.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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