Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling

Abstract

The concept advanced by Berridge and colleagues that intracellular Ca 2+ -stores can be mobilized in an agonist-dependent and messenger (IP 3 )-mediated manner has put Ca 2+ -mobilization at the center stage of signal transduction mechanisms. During the late 1980s, we showed that Ca 2+ -stores can be mobilized by two other messengers unrelated to inositol trisphosphate (IP 3 ) and identified them as cyclic ADP-ribose (cADPR), a novel cyclic nucleotide from NAD, and nicotinic acid adenine dinucleotide phosphate (NAADP), a linear metabolite of NADP. Their messenger functions have now been documented in a wide range of systems spanning three biological kingdoms. Accumulated evidence indicates that the target of cADPR is the ryanodine receptor in the sarco/endoplasmic reticulum, while that of NAADP is the two pore channel in endolysosomes.As cADPR and NAADP are structurally and functionally distinct, it is remarkable that they are synthesized by the same enzyme. They are thus fraternal twin messengers. We first identified the Aplysia ADP-ribosyl cyclase as one such enzyme and, through homology, found its mammalian homolog, CD38. Gene knockout in mice confirms the important roles of CD38 in diverse physiological functions from insulin secretion, susceptibility to bacterial infection, to social behavior of mice through modulating neuronal oxytocin secretion. We have elucidated the catalytic mechanisms of the Aplysia cyclase and CD38 to atomic resolution by crystallography and site-directed mutagenesis. This article gives a historical account of the cADPR/NAADP/CD38-signaling pathway and describes current efforts in elucidating the structure and function of its components.cyclic ADP-ribose, cADPR, NAADP, nicotinic acid adenine dinucleotide phosphate, CD38, ADP-ribosyl cyclase, Calcium mobilization and signaling Citation:Lee H C. Cyclic ADP-ribose and NAADP: fraternal twin messengers for calcium signaling. Sci China Life Sci, 2011Sci, , 54: 699 -711, doi: 10.1007 In 1983, Berridge and colleagues published a study showing that agonists, such as carbachol, can activate Ca 2+ release from non-mitochondrial Ca 2+ stores and the effect is mediated by a Ca 2+ messenger, inositol 1,4,5-trisphosphate (IP 3 ) [1]. The targeted Ca 2+ stores were later identified as the endoplasmic reticulum (ER), which has since been shown to be the major intracellular Ca 2+ stores. This seminal study ushered in the current field of Ca 2+ signaling as we know it and has made the field center stage. IP 3 is derived from a phospholipid, phosphatidyl inositol 4,5-bisphosphate, present on the cytoplasmic side of the plasma membrane. Agonist binding to its specific receptor leads to activation of phospholipase C and the hydrolysis of the phospholipid, releasing the head group that is IP 3 . The structure of IP 3 is shown in Figure 1. It has three phosphates on the inositol ring. Both the number of phosphates and the position of the phosphates are critical to the binding of IP 3 to its receptor in the ER. The space-filling model of IP 3 shown in Figu...

NAD+ Levels Control Ca2+ Store Replenishment and Mitogen-induced Increase of Cytosolic Ca2+ by Cyclic ADP-ribose-dependent TRPM2 Channel Gating in Human T Lymphocytes

“…Production of intracellular ADPR is due to the enhanced NAD ϩ -glycohydrolase activity of CD38 in the presence of an increased concentration of its substrate NAD ϩ . Although CD38 is an ectoenzyme, with the active site facing the extracellular environment (59,60), its expression/activation in cells leads to the intracellular accumulation of cADPR, the product of its ADP-ribosyl cyclase activity (20,(61)(62)(63), and of ADPR, the product of its NAD ϩ -glycohydrolase activity (16,45).…”

Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) as Messengers for Calcium Mobilization

“…Multiple defects are detected in the knock-out mice, including impairment in insulin secretion (85), increased susceptibil- ity to bacterial infection (84) 11). It is also noteworthy that the ubiquitous "NADase" activity observed in tissues that had no known function is greatly depressed after CD38 ablation (84), clarifying a long-time enigma.…”

Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca2+signaling pathway

“…However, if the catalytic domain of CD38 is phosphorylated by protein kinase A (PKA), this domain should be in the cytosol to directly cyclize NAD, thereby synthesizing cAD-PR intracellularly. This suggests that although CD38 is believed to be a type-Ⅱ protein, at least a portion of the total CD38 is expressed as a type-Ⅲ membrane protein with its C-terminal catalytic domain sitting in the cyto-sol [53] . Since the number of positive charges that determine the polarity of membrane protein is equal on each side of the CD38 transmembrane segment, studies from protease digestion [54] and electron microscopy [55] showed that the nuclear CD38 might be a type-Ⅲ membrane protein.…”