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Science China Life Sciences

, Volume 54, Issue 8, pp 699–711

First Online: 24 July 2011Received: 11 May 2011Accepted: 10 June 2011


The concept advanced by Berridge and colleagues that intracellular Ca-stores can be mobilized in an agonist-dependent and messenger IP3-mediated manner has put Ca-mobilization at the center stage of signal transduction mechanisms. During the late 1980s, we showed that Ca-stores can be mobilized by two other messengers unrelated to inositol trisphosphate IP3 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.

Keywordscyclic ADP-ribose cADPR NAADP nicotinic acid adenine dinucleotide phosphate CD38 ADP-ribosyl cyclase Calcium mobilization and signaling This article is published with open access at

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Autor: Hon Cheung Lee


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