NAADP: A Universal Ca²⁺ Trigger

Andreas H. Guse^1* and Hon Cheung Lee²

¹ The Calcium Signaling Group, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20146 Hamburg, Germany.
² Department of Physiology, The Hong Kong University, 4/F Lab Block, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong.

Abstract: Cells possess multiple calcium ion (Ca²⁺) stores and multiple messenger molecules to mobilize them. These include D-myo-inositol 1,4,5-trisphosphate (IP₃), cyclic adenosine diphosphoribose (cADPR), and the most recently identified Ca²⁺-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), which acts on a wide spectrum of cells, from plant cells to mammalian cells. Accumulating evidence indicates that NAADP targets both acidic (lysosome-like) Ca²⁺ stores and endoplasmic reticular stores. Recent studies in invertebrate and mammalian cells suggest that NAADP provides an initiating Ca²⁺ signal, which is amplified by cADPR- or IP₃-dependent mechanisms (or both) through Ca²⁺-induced Ca²⁺ release. Diverse stimuli activate a rapid rise of endogenous NAADP concentration, resulting in severalfold increases of NAADP over basal values within seconds. The enzyme CD38 can catalyze both the synthesis and hydrolysis of NAADP, making it ideal for effecting the rapid metabolism of NAADP. The crystal structure of CD38 and the structures of its various substrate complexes have now been determined, clarifying the mechanism of its multifunctional catalysis. We anticipate that these advances will lead to the unmasking of all the key components of the Ca²⁺ signaling pathway mediated by NAADP.

* Corresponding author. E-mail, guse{at}uke.uni-hamburg.de

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