Review
The CD38/cyclic ADP-ribose system: A topological paradox

https://doi.org/10.1016/S1357-2725(97)00062-9Get rights and content

Abstract

CD38 was first identified as a lymphocyte differentiation antigen that showed typical properties of an orphan receptor involved in many programs of cell proliferation and activation. However, CD38 proved also to be a bifunctional ectoenzyme that catalyzes the transient formation of cyclic ADP-ribose (cADPR) in a variety of cell types. This property raises many intriguing and so far unanswered questions, since cADPR is a new second messenger molecule directly involved in the control of calcium homeostasis by means of receptor-mediated release of calcium from ryanodine-sensitive intracellular stores. The relationship between receptor-like and enzymatic properties of CD38 is still unknown. The apparent topological paradox of ectocellular synthesis and intracellular activity of cADPR might be explained by: (a) influx of cADPR across the plasma membrane to reach its target stores, as suggested by experiments on cerebellar granule cells; and (b) NAD+-induced internalization, following membrane oligomerization, of CD38 with consequent partial import of cADPR metabolism to an intracellular compartment, as recently observed in lymphoid B cells. These two distinct mechanisms and other potential ones (e.g. binding of ectocellularly formed cADPR to cell surface receptors and initiation of signal-transducing pathways across the plasmamembrane) seem to be paradigmatic of processes affecting different types of cells. Although in some biological systems, such as Aplysia and sea urchin egg, cADPR metabolism is restricted to the intracellular environment, in mammalian cells the CD38/cADPR system provides new challenges in terms of subcellular compartmentation and qualifies as an unusual example of “ectobiochemistry” with potential, still unrecognized, properties of cellular regulation.

References (108)

  • A.C. Greenlund et al.

    Interferon-γ induces receptor dimerization in solution and on cells

    J. Biol. Chem.

    (1993)
  • L. Guida et al.

    Structural role of disulfide bridges in the cyclic ADP-ribose related bifunctional ectoenzyme CD38

    FEBS Lett.

    (1995)
  • Y. Hirata et al.

    ADP ribosyl cyclase activity of a novel bone marrow stromal cell surface molecule, BST-1

    FEBS Lett.

    (1994)
  • I. Kato et al.

    Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic β cells

  • U.H. Kim et al.

    Function of NAD glycohydrolase in ADP-ribose uptake from NAD by human erythrocytes

    Biochim. Biophys. Acta

    (1993)
  • K. Kontani et al.

    NAD glycohydrolase specifically induced by retinoic acid in human leukemic HL-60 cells: identification of the NAD glycohydrolase as leukocyte cell surface antigen CD38

    J. Biol. Chem.

    (1993)
  • J.F. Kuemmerle et al.

    Agonist-stimulated cyclic ADP ribose

  • H.C. Lee et al.

    Structural determination of a cyclic metabolite of NAD+ with intracellular Ca2+ mobilizing activity

    J. Biol. Chem.

    (1989)
  • H.C. Lee

    Potentiation of calcium- and caffeine-induced calcium release by cyclic ADP-ribose

    J. Biol. Chem.

    (1993)
  • H.C. Lee et al.

    Production and hydrolysis of cyclic ADP-ribose at the outer surface of human erythrocytes

    Biochem. Biophys. Res. Commun.

    (1993)
  • H.C. Lee

    Cyclic ADP-ribose: a new member of a super family of signalling cyclic nucleotides

    Cell. Signal.

    (1994)
  • H.C. Lee et al.

    A derivative of NADP mobilizes calcium stores insensitive to inositol trisphosphate and cyclic ADP-ribose

    J. Biol. Chem.

    (1995)
  • H.C. Lee et al.

    Cyclic ADP-ribose and its metabolic enzymes

    Biochimie

    (1995)
  • H.C. Lee et al.

    Sensitization of calcium-induced calcium release by cyclic ADP-ribose and calmodulin

    J. Biol. Chem.

    (1995)
  • F. Lund et al.

    Murine CD38: an immunoregulatory ectoenzyme

    Immunol. Today

    (1995)
  • F. Malavasi et al.

    Characterization of a murine monoclonal antibody specific for human early lymphohemopoietic cells

    Hum. Immunol.

    (1984)
  • F. Malavasi et al.

    Human CD38: a glycoprotein in search of a function

    Immunol. Today

    (1994)
  • A. Marcilla et al.

    Identification of the major tyrosine kinase substrate in signaling complexes formed after engagement of Fc receptors

    J. Biol. Chem.

    (1995)
  • V. Mészàros et al.

    The kinetics of cyclic ADP-ribose formation in heart muscle

    Biochem. Biophys. Res. Commun.

    (1995)
  • M. Mizuguchi et al.

    Neuronal localization of CD38 antigen in the human brain

    Brain Res.

    (1995)
  • H. Müller-Steffner et al.

    Mechanistic implications of cyclic ADP-ribose hydrolysis and methanolysis catalyzed by calf spleen NAD+ glycohydrolase

    Biochem. Biophys. Res. Commun.

    (1994)
  • K. Nata et al.

    The structure of the Aplysia kurodai gene encoding ADP-ribosyl cyclase, a second messenger enzyme

    Gene

    (1995)
  • H. Nishina et al.

    Cell surface antigen CD38 identified as ecto-enzyme of NAD+ glycohydrolase has hyaluronate-binding activity

    Biochem. Biophys. Res. Commun.

    (1994)
  • D.J. States et al.

    Similarities in amino acid sequences of Aplysia ADP-ribosyl cyclase and human lymphocyte antigen CD38

    Trends Biochem. Sci.

    (1992)
  • R.J. Summerhill et al.

    Human lymphocyte antigen CD38 catalyzes the production of cyclic ADP-ribose

    FEBS Lett.

    (1993)
  • K. Takahashi et al.

    Accumulation of cyclic ADP-ribose measured by a specific radioimmunoassay in differentiated human leukemic HL-60 cells with all-trans-retinoic acid

    FEBS Lett.

    (1995)
  • S. Takasawa et al.

    Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38 and inhibition of the hydrolysis by ATP

    J. Biol. Chem.

    (1993)
  • S. Takasawa et al.

    Requirement of calmodulin-dependent protein kinase II in cyclic ADP-ribose mediated intracellular Ca2+ mobilization

    J. Biol. Chem.

    (1995)
  • S. Tanaka et al.

    Tyrosine phosphorylation and translocation of the c-cbl protein after activation of tyrosine kinase signaling pathways

    J. Biol. Chem.

    (1995)
  • A. Tohgo et al.

    Essential cysteine residues for cyclic ADP-ribose synthesis and hydrolysis by CD38

    J. Biol. Chem.

    (1994)
  • S. Umar et al.

    Post-translational modification of CD38 protein into a high molecular weight form alters its catalytic properties

    J. Biol. Chem.

    (1996)
  • T.F. Walseth et al.

    Synthesis and characterization of antagonists of cyclic ADP-ribose

    Biochim. Biophys. Acta

    (1993)
  • T.F. Walseth et al.

    Identification of cyclic ADP-ribose-binding proteins by photoaffinity labeling

    J. Biol. Chem.

    (1993)
  • R. Aarhus et al.

    ADP-ribosyl cyclase and CD38 catalyze the synthesis of a calcium mobilizing metabolite from NADP

    J. Biol. Chem.

    (1995)
  • M. Alessio et al.

    CD38 molecule: structural and biochemical analysis of human T lymphocytes, thymocytes and plasma cells

    J. Immunol.

    (1990)
  • C.M. Ausiello et al.

    CD38 ligation induces discrete cytokine mRNA expression in human cultured lymphocytes

    Eur. J. Immunol.

    (1995)
  • S.I. Belli et al.

    Divalent cations stabilize the conformation of plasma cell membrane glycoprotein PC-1 (alkaline phosphodiesterase 1)

    Biochem. J.

    (1994)
  • S.L. Belli et al.

    Identification and characterization of a soluble form of the plasma cell membrane glycoprotein PC-1 (5′-nucleotide phosphodiesterase)

    Eur. J. Biochem.

    (1993)
  • M.J. Berridge

    A tale of two messengers

    Nature

    (1989)
  • M.J. Berridge

    Inositol triphosphate and calcium signalling

    Nature

    (1993)
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