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A new function for CD38/ADP-ribosyl cyclase in nuclear Ca2+ homeostasis

Nature Cell Biology volume 1, pages 409–414 (1999)Cite this article

Abstract

Nucleoplasmic calcium ions (Ca2+) influence nuclear functions as critical as gene transcription, apoptosis, DNA repair, topoisomerase activation and polymerase unfolding. Although both inositol trisphosphate receptors and ryanodine receptors, types of Ca2+ channel, are present in the nuclear membrane, their role in the homeostasis of nuclear Ca2+ remains unclear. Here we report the existence in the inner nuclear membrane of a functionally active CD38/ADP-ribosyl cyclase that has its catalytic site within the nucleoplasm. We propose that the enzyme catalyses the intranuclear cyclization of nicotinamide adenine dinucleotide to cyclic adenosine diphosphate ribose. The latter activates ryanodine receptors of the inner nuclear membrane to trigger nucleoplasmic Ca2+ release.

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Figure 1: Confocal microscopic localization of CD38/ADP-ribosyl cyclase to the nuclear membrane.
Figure 2: Co-localization of RyRs and CD38 in the inner nuclear membrane.
Figure 3: Peripheral nuclear localization of a CD38–EGFP fusion protein is driven by full-length, not truncated, CD38.
Figure 4: Immunolocalization of CD38 in isolated nuclear membranes.
Figure 5: Topology of CD38 at the inner nuclear membrane.
Figure 6: ADP-ribosyl-cyclase activity in isolated nuclear membranes.
Figure 7: Effects of NAD+, cADPr and InsP3 on nucleoplasmic Ca2+ concentration.

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References

  1. Malviya, A. N. & Rogue, P. J. ‘‘Tell me where is calcium bred’’: clarifying the roles of nuclear calcium. Cell 92, 17–23 ( 1998).

    Article  CAS  Google Scholar 

  2. Santella, L. & Carafoli, E. Calcium signaling in the cell nucleus . FASEB J. 11, 1091–1109 (1997).

    Article  CAS  Google Scholar 

  3. Al-Mohanna, F. A. et al. The nucleus is insulated from large cytosolic calcium ion changes. Nature 367, 745– 750 (1994).

    Article  CAS  Google Scholar 

  4. Perez-Terzic, C., Stehno-Bittel, L. & Clapham, D. E. Nucleoplasmic and cytoplasmic differences in the fluorescent properties of calcium indicator fluo-3. Cell Calcium 21, 275–282 ( 1997).

    Article  CAS  Google Scholar 

  5. Fox, J. L., Burgstahler, A. D. & Nathanson, M. H. Mechanism of long-range Ca2+ signaling in the nucleus of isolated rat hepatocytes. Biochem J. 326, 491–495 (1997).

    Article  CAS  Google Scholar 

  6. Gerasimenko, O. V. et al. ATP-dependent accumulation and inositol triphosphate or cyclic ADP ribose-mediated release of calcium from the nuclear envelope. Cell 80, 439–444 ( 1995).

    Article  CAS  Google Scholar 

  7. Hennager, D. J., Welsh, M. J. & DeLisle, S. Changes in either cytosolic or nuleoplasmic inositol 1,4,5-trisphosphate levels can control nuclear calcium concentration. J. Biol. Chem. 270, 4959–4962 (1995).

    Article  CAS  Google Scholar 

  8. Santella, L. & Kyozuka, K. Calcium release into the nucleus by 1,4,5-trisphosphate and cyclic ADP-ribose gated channels induced the resumption of meiosis in starfish oocytes. Cell Calcium 22, 1–10 (1997).

    Article  Google Scholar 

  9. Mehta, M., Shahid, U. & Malavasi, F. Human CD38, a cell surface protein with multiple functions . FASEB J. 10, 1408–1417 (1996).

    Article  CAS  Google Scholar 

  10. Zaidi, M. et al. A ryanodine receptor-like molecule expressed in the osteoclast plasma membrane functions in extracellular Ca2+ sensing. J. Clin. Invest. 96, 1582–1590 (1995).

    Article  CAS  Google Scholar 

  11. Morita, K., Kitayama, S. & Dohi, T. Stimulation of cyclic ADP-ribose synthesis by acetylcholine and its role in catecholamine release in bovine adrenal chromaffin cells. J. Biol. Chem. 272, 21002–21009 (1997).

    Article  CAS  Google Scholar 

  12. Anandathreerthvardha, H. K. et al. Localization of multiple forms of inducible cytochromes P 450 in rat liver mitochondria: immunological characteristics and patterns of xenobiotic substrate metabolism. Arch. Biochem. Biophys. 339, 136–150 (1997).

    Article  Google Scholar 

  13. Humbert, J. P. et al. Inositol 1,4,5,-trisphosphate receptor is located to the inner nuclear membrane vindicating regulation of nuclear Ca2+ signaling by inositol 1,4,5-trisphosphate. J. Biol. Chem. 271, 478–485 ( 1996).

    Article  CAS  Google Scholar 

  14. Matter, N. & Malviya, A. N. Calcium transported to isolated rat liver nuclei by nicotinamide adenine dinucleotide is insensitive to thapsigargin . FEBS Lett. 387, 85–88 (1996).

    Article  CAS  Google Scholar 

  15. Malviya, A. N., Rogue, P. & Vincendon, G. Sterospecific inositol 1,4,5-[32P] trisphosphate binding to isolated rat liver nuclei. Evidence for inositol trisphosphate receptor mediated calcium release from the nucleus. Proc. Natl Acad. Sci. USA. 87, 9270– 9274 (1990).

    Article  CAS  Google Scholar 

  16. Nicotera, P. et al. An inositol 1,4,5-trisphosphate-sensitive Ca2+ pool in liver nuclei. Proc. Natl Acad. Sci. USA. 87, 6858–6862 (1990).

    Article  CAS  Google Scholar 

  17. Mak, D. O. D., & Foskett, J. K. Single-channel inositol 1,4,5-trisphosphate receptor currents revealed by patch clamp of isolated Xenopus oocyte nuclei. J. Biol. Chem. 269, 29375–29378 (1994).

    CAS  PubMed  Google Scholar 

  18. Capitani, S. et al. Uptake and phosphorylation of phosphatidyl inositol by rat liver nuclei: role of phosphatidyl inositol transfer protein. Biochim. Biophys. Acta. 1044, 193– 200 (1990).

    Article  CAS  Google Scholar 

  19. Payraste, B. et al. A differential localization of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix. J. Biol. Chem. 267, 5078–5084 ( 1992).

    Google Scholar 

  20. Asano, M. et al. Purification and characterization of nuclear phospholipase C specific for phosphoinositides. J. Biol. Chem. 269, 12360–12366 (1994).

    CAS  PubMed  Google Scholar 

  21. Hardingham, G. E. et al. Distinct functions of nuclear and cytoplasmic Ca2+ in the control of gene expression. Nature 285, 260 (1996).

    Google Scholar 

  22. Ginty, D. D., Bonni, A. & Greenberg, M. E. Nerve growth factor activates a ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 77, 713–725 (1996).

    Article  Google Scholar 

  23. Hill, C. S. & Treisman, R. Transcription regulation by extracellular signals: mechanisms and specificity. Cell 80, 199–211 (1995).

    Article  CAS  Google Scholar 

  24. Larea, L. S. & McNamara, O. J. Ionotropic glutamate receptor subtypes activate c-fos transcription by distinct calcium-requiring intracellular signaling pathways. Neuron 10, 31–41 (1993).

    Article  Google Scholar 

  25. Adebanjo, O. A. et al. Mode of action of interleukin-6 on mature osteoclasts. Novel interactions with extracellular Ca2+ sensing in the regulation of osteoclastic bone resorption. J. Cell Biol. 142, 1347–1356 (1998).

    Article  CAS  Google Scholar 

  26. Chawla, S. et al. CBP: a signal-regulated transcriptional co-activator controlled by nuclear calcium and CaM kinase IV. Science 281, 1505–1509 (1998).

    Article  CAS  Google Scholar 

  27. Biswas G. et al. Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J 18, 522 –533 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the NIH (RO1-AG14917, to M.Z., and R37-CA22762, to N.G.A.) and by the Department of Veterans Affairs (Merit Review to M.Z.). We thank I. MacIntyre and T. Davies for support.

Correspondence and requests for materials should be addressed to M.Z.

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Authors and Affiliations

  1. Department of Medicine, Medical College of Pennsylvania School of Medicine and Veterans Affairs Medical Center, Philadelphia , 19104, Pennsylvania, USA

    Olugbenga A. Adebanjo, Anatoliy P. Koval, Baljit S. Moonga, Li Sun, Bali R. Sodam, Peter J. R. Bevis & Solomon Epstein

  2. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylavania, USA

    Hindupur K. Anandatheerthavarada, Gopa Biswas & Narayan G. Avadhani

  3. The Physiological Laboratory, University of Cambridge , Cambridge, CB2 3EG, UK

    Christopher L.-H. Huang

  4. University of Wales College of Medicine, Heath Park,, Cardiff, CF14 4XN, UK

    F. Anthony Lai

  5. Division of Endocrinology, Mailbox 1055, Mount Sinai School of Medicine, One Gustave Levy Place, New York, 10029, New York, USA

    Olugbenga A. Adebanjo, Baljit S. Moonga, Li Sun, Bali R. Sodam, Peter J. R. Bevis & Mone Zaidi

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  1. Olugbenga A. Adebanjo
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Correspondence to Mone Zaidi.

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Adebanjo, O., Anandatheerthavarada, H., Koval, A. et al. A new function for CD38/ADP-ribosyl cyclase in nuclear Ca2+ homeostasis. Nat Cell Biol 1, 409–414 (1999). https://doi.org/10.1038/15640

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