Abstract
Calcium (Ca2+) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca2+ signaling pathways to couple the Ca2+ signal to their biochemical machinery. Ca2+ influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca2+ from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca2+. Inside the cell, Ca2+ is controlled by the buffering action of cytosolic Ca2+-binding proteins and by its uptake and release by mitochondria. The uptake of Ca2+ in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca2+ from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na+/Ca2+ exchanger in the plasma membrane also participates in the control of neuronal Ca2+. The impaired ability of neurons to maintain an adequate energy level may impact Ca2+ signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca2+ signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca2+ signaling in the most important neurological disorders will then be considered.
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Acknowledgments
The original work by the authors has been supported over the years by grants from the Italian Ministry of University and Research (FIRB2001 to E.C., PRIN 2003, 2005 and 2008 to M.B), the Telethon Foundation (Project GGP04169 to M.B.), the FP6 program of the European Union (FP6 Network of Excellence NeuroNe, LSH-2003-2.1.3-3 to E.C. and Integrated Project Eurohear to E.C.), the Human Frontier Science Program Organization to E.C., the ERANet-Neuron (nEUROsyn), and CARIPARO Foundation to E.C, the Italian National Research Council (Agenzia 2000, CNR) and by grant from the University of Padova (Progetto di Ateneo 2008 CPDA082825) to M.B. Tito Calì is supported by the University of Padova (Progetto Giovani GRIC128SP0, Bando 2012). We apologize to many authors who have published substantial scientific contributions in the field of this specific Ca2+ research whose work could not or not sufficiently be cited here. This is due to space restrictions. Figures 1, 3 and 5 were produced using ServierMedical Art (http://www.servier.com/serviermedical-art/powerpoint-image-bank).
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Brini, M., Calì, T., Ottolini, D. et al. Neuronal calcium signaling: function and dysfunction. Cell. Mol. Life Sci. 71, 2787–2814 (2014). https://doi.org/10.1007/s00018-013-1550-7
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DOI: https://doi.org/10.1007/s00018-013-1550-7