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

作　　者：Hon Cheung LEE 

机构地区：[1]Department of Physiology,University of Hong Kong

出　　处：《Science China(Life Sciences)》2011年第8期699-711,共13页中国科学（生命科学英文版）

基　　金：supported by the Research Grants Council of Hong Kong(Grant Nos.769107,768408, 769309 and 770610);the National Natural Science Foundation of China/the Research Grants Council of Hong Kong(Grant No.N_HKU 722/08)

摘　　要：The concept advanced by Berridge and colleagues that intracellular Ca2+-stores can be mobilized in an agonist-dependent and messenger(IP3)-mediated manner has put Ca 2+-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2+-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.The concept advanced by Berridge and colleagues that intracellular Ca2＋-stores can be mobilized in an agonist-dependent and messenger（IP3）-mediated manner has put Ca 2＋-mobilization at the center stage of signal transduction mechanisms.During the late 1980s,we showed that Ca2＋-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.

关 键 词：cyclic ADP-ribose CADPR NAADP nicotinic acid adenine dinucleotide phosphate CD38 ADP-ribosyl cyclase Calcium mobilization and signaling 

分 类 号：Q257[生物学—细胞生物学] O629.1[理学—有机化学]