MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP

Sarah Krukenberg, Franziska Möckl, Mariella Weiß, Patrick Dekiert, Melanie Hofmann, Fynn Gerlach, Kai J. Winterberg, Dejan Kovacevic, Imrankhan Khansahib, Berit Troost, Macarena Hinrichs, Viviana Granato, Mikolaj Nawrocki, Tobis Hub, Volodymyr Tsvilovskyy, Rebekka Medert, Lena-Marie Woelk, Fritz Förster, Huan Li, René Werner, Marcus Altfeld, Samuel Huber, Oliver Biggs Clarke, Marc Freichel, Björn-Philipp Diercks, Chris Meier and Andreas H. Guse ()
Additional contact information
Sarah Krukenberg: University of Hamburg
Franziska Möckl: University Medical Center Hamburg-Eppendorf
Mariella Weiß: University Medical Center Hamburg-Eppendorf
Patrick Dekiert: University of Hamburg
Melanie Hofmann: University of Hamburg
Fynn Gerlach: University Medical Center Hamburg-Eppendorf
Kai J. Winterberg: University Medical Center Hamburg-Eppendorf
Dejan Kovacevic: University Medical Center Hamburg-Eppendorf
Imrankhan Khansahib: University Medical Center Hamburg-Eppendorf
Berit Troost: University Medical Center Hamburg-Eppendorf
Macarena Hinrichs: University Medical Center Hamburg-Eppendorf
Viviana Granato: University Medical Center Hamburg-Eppendorf
Mikolaj Nawrocki: University Medical Center Hamburg-Eppendorf
Tobis Hub: Heidelberg University
Volodymyr Tsvilovskyy: Heidelberg University
Rebekka Medert: Heidelberg University
Lena-Marie Woelk: University Medical Center Hamburg-Eppendorf
Fritz Förster: University Medical Center Hamburg-Eppendorf
Huan Li: Columbia University Irving Medical Center
René Werner: University Medical Center Hamburg-Eppendorf
Marcus Altfeld: University Medical Center Hamburg-Eppendorf
Samuel Huber: University Medical Center Hamburg-Eppendorf
Oliver Biggs Clarke: Columbia University Irving Medical Center
Marc Freichel: Heidelberg University
Björn-Philipp Diercks: University Medical Center Hamburg-Eppendorf
Chris Meier: University of Hamburg
Andreas H. Guse: University Medical Center Hamburg-Eppendorf

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Upon stimulation of membrane receptors, nicotinic acid adenine dinucleotide phosphate (NAADP) is formed as second messenger within seconds and evokes Ca2+ signaling in many different cell types. Here, to directly stimulate NAADP signaling, MASTER-NAADP, a Membrane permeAble, STabilized, bio-rEversibly pRotected precursor of NAADP is synthesized and release of its active NAADP mimetic, benzoic acid C-nucleoside, 2’-phospho-3’F-adenosine-diphosphate, by esterase digestion is confirmed. In the presence of NAADP receptor HN1L/JPT2 (hematological and neurological expressed 1-like protein, HN1L, also known as Jupiter microtubule-associated homolog 2, JPT2), this active NAADP mimetic releases Ca2+ and increases the open probability of type 1 ryanodine receptor. When added to intact cells, MASTER-NAADP initially evokes single local Ca2+ signals of low amplitude. Subsequently, also global Ca2+ signaling is observed in T cells, natural killer cells, and Neuro2A cells. In contrast, control compound MASTER-NADP does not stimulate Ca2+ signaling. Likewise, in cells devoid of HN1L/JPT2, MASTER-NAADP does not affect Ca2+ signaling, confirming that the product released from MASTER-NAADP is a bona fide NAADP mimetic.

Date: 2024
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DOI: 10.1038/s41467-024-52024-y

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