Two-pore channels and NAADP-mediated endolysosomal Ca2+ signaling in health and disease. (360G-Wellcome-102828_Z_13_Z)

Stimulus-dependent combinations of multiple Ca2+-mobilizing messengers generate specific spatio-temporal Ca2+ signals which are decoded into distinct cellular responses. Cracking this Ca2+ code requires a detailed understanding of the spatial/temporal choreography of the messengers, proteins and organelles that generate these Ca2+ signatures. The three major messengers regulating Ca2+ signalling are inositol trisphosphate (IP3), cyclic ADP-ribose (cADPR) and nicotinic adenine dinucleotide pho sphate (NAADP). Whilst IP3 and cADPR activate Ca2+-release channels of the neutral endoplasmic reticulum (ER), NAADP is unique in evoking Ca2+ release from acidic endo-lysosomes: a new role for these important organelles. Our recent work suggests that two-pore channels (TPCs) a novel family of endolysosomal channels are the target Ca2+ channels for NAADP. Whereas IP3 signalling is relatively well understood, NAADP signalling is less clearly defined. This proposal seeks to clarify fundamen tal aspects of NAADP signalling, particularly the mechanisms by which cellular stimuli induce changes in NAADP levels, how NAADP mobilizes Ca2+ from endo-lysosomal stores (in particular the precise roles of TPCs), and the specific roles of endo-lysosomal Ca2+ stores in (patho)physiological processes.