28] Synthesis and hydrolysis of cyclic ADP-ribose by human leukocyte antigen CD38: Inhibition of hydrolysis by ATP and physiological significance

Abstract

Cyclic ADP-ribose (cADPR) serves as a second messenger for Ca2+ mobilization from the endoplasmic reticulum via the ryanodine-like receptor (RyR), and this cADPR-mediated Ca2+ release from the RyR is activated by Ca2+/calmodulin-dependent protein kinase II. Cyclic ADP-ribose also acts as a modulator of Ca2+-induced Ca2+ release in a variety of mammalian cells. Cyclic ADP-ribose is synthesized from NAD+ by ADP-ribosylcyclase and hydrolyzed to ADP-ribose (ADPR) by cADPR hydrolase. This chapter demonstrates that the lymphocyte antigen, CD38, and the bone marrow stromal cell antigen 1, BST-1, show both ADP-ribosylcyclase and cADPR hydrolase activities. The chapter focuses on the mammalian bifunctional ADP-ribosylcyclase/cADPR hydrolase, CD38, and its regulation. CD38 mRNA is detected in various rat and human tissues and cells including spleen, liver, heart, thymus, thyroid gland, ileum, jejunum, colon, cerebellum, salivary gland, and islets. CD38 mRNA is expressed in streptozotocin/nicotinamide-induced insulinomas, which retain sensitivity to glucose and contain as much insulin mRNA as normal islets, but not in rat insulinoma-derived RINm5F cells, which do not release Ca2+ in response to cADPR, synthesize and secrete very little insulin, and show negligible sensitivity to glucose. Rat BST-1 mRNA is detected in islets, kidney, spleen, heart, thymus, ileum, jejunum, and salivary gland by Northern blot analysis. Reverse transcription–polymerase chain reaction (RT–PCR) reveals that BST-1 mRNA is expressed not only in islets and streptozotocin/nicotinamide-induced insulinomas but also in R1Nm5F cells.