THE CD38 CYCLIC ADP-RIBOSE SYSTEM - A TOPOLOGICAL PARADOX/

CD38 was first identified as a lymphocyte differentiation antigen that showed typical properties of an orphan receptor involved in many prog rams of cell proliferation and activation. However, CD38 proved also t o 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 i s a new second messenger molecule directly involved in the control of calcium homeostasis by means of receptor-mediated release of calcium f rom 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 intracellul ar activity of cADPR might be explained by: (a) influx of cADPR across the plasma membrane to reach its target stores, as suggested by exper iments on cerebellar granule cells; and (b) NAD(+)-induced internaliza tion, following membrane oligomerization, of CD38 with consequent part ial import of cADPR metabolism to an intracellular compartment, as rec ently observed in lymphoid B cells. These two distinct mechanisms and other potential ones (e.g. binding of ectocellularly formed cADPR to c ell surface receptors and initiation of signal-transducing pathways ac ross the plasmamembrane) seem to be paradigmatic of processes affectin g different types of cells. Although in some biological systems, such as Aplysia and sea urchin egg, cADPR metabolism is restricted to the i ntracellular environment, in mammalian cells the CD38/cADPR system pro vides new challenges in terms of subcellular compartmentation and qual ifies as an unusual example of ''ectobiochemistry'' with potential, st ill unrecognized, properties of cellular regulation. (C) 1997 Elsevier Science Ltd.