Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Ca2+ signals regulate a wide range of physiological processes. Intracellular Ca2+ stores can be mobilized in response to extracellular stimuli via a range of signal transduction mechanisms, often involving recruitment of diffusible second messenger molecules. The Ca2+ mobilizing messengers InsP(3) and cADPR release Ca2+ from the endoplasmic reticulum via InsP(3) and ryanodine receptors, respectively, while a third messenger, NAADP, releases Ca2+ from acidic endosomes and lysosomes. Bidirectional communication between the ER and acidic organelles has functional relevance for endolysosomal function as well as for the generation of Ca2+ signals. The two-pore channels (TPCs) are currently strong candidates for being key components of NAADP-regulated Ca2+ channels. Ca2+ signals have been shown to play important roles in embryonic development and cell differentiation; however, much remains to be established about the exact signalling mechanisms involved. Investigation of the role of NAADP and TPCs in development and differentiation is still at an early stage, but recent studies have suggested that they play important roles at key developmental stages in vivo and are important mediators of differentiation of neurons, skeletal muscle cells and osteoclasts in vitro. NAADP signals and TPCs have also been implicated in autophagy, an important process in differentiation. Moreover, potential links between TPC2 and cancer have been recently identified. Further studies will be required to identify the precise mechanisms of action of TPCs and their link with NAADP signalling, and to relate these to their roles in differentiation and other key developmental processes in the cell and organism.