NAADP: A New Second Messenger Ca2+ Mobilizator and Autophagy Regulator

Abstract

In the past few years, the inositol triphosphate (IP3) and adenosine diphosphate ribose (cADPR) were well stablished as intracelullar messengers that interact with the IP3R and RyR, respectively. Recently, a novel second messenger was described, the NAADP (nicotinic acid adenine dinucleotide phosphate), which induces a significant mobilization of intracellular calcium (Ca2+). Evidences show that NAADP acts on lysosomes, releasing Ca2+ from this compartment and influencing cell signaling and homeostasis. Ca2+ has been described not only as an intracellular messenger in physiological processes but also as a element of the cell death cascades. There are at least two types of cell death: apoptosis and necrosis, which have different morphological and biochemical characteristics. More recently, autophagy, initially described as a type of programmed cell death, has been presented as a mechanism that precedes apoptosis or as cell survival process against an aggressive stimulus. However, it is not known whether NAADP can induce or modulate the mechanisms of apoptosis and autophagy. Ca2+ buffering mechanisms are involved in neurodegeneration and the study of NAADP is also needed, since it may modulate the neurotransmission as well as the apoptotic and autophagic pathways. Therefore, the objective of this work is to investigate the intracellular signaling mediated by NAADP in neurons and glia and the relationship with apoptotic and autophagic signaling. For this purpose, we will use real time real space high resolution fluorescence microscopy. Apoptosis and autophagy will be evaluated by flow cytometry, electron microscopy and the expression of genes and proteins related to these pathways which will be analyzed by molecular biology techniques.