Store-operated calcium entry in neural cells. A role in Charcot-Marie-Tooth disease

Résumé

Calcium (Ca2+) is a universal second messenger in eukaryotic cells that regulates numerous cellular processes. Cells have developed highly specific mechanisms to control the concentration of Ca2+ in each cellular location. The store-operated calcium entry (SOCE) is a mechanism that allows Ca2+ influx from the external medium into the cytosol when the ER-Ca2+ levels decrease, being one of its functions the replenishment of intracellular Ca2+ stores. We have addressed the role of SOCE in different neural cells, neuroblastoma cells and primary mouse cortical neurons. In neuroblastoma cells, we have found that SOCE activity is facilitated by mitochondrial Ca2+ uptake, preventing its Ca2+-dependent inactivation and Ca2+ entry through SOC channels impacts on cell metabolism, stimulating mitochondrial respiration. SOCE-driven Ca2+ entry and SOCEstimulated respiration were impaired in a cellular model of Charcot-Marie-Tooth disease caused by GDAP1 gene, suggesting that a failure in bioenergetics may be a pathological mechanism involved in the disease. In neurons, the existence of SOCE pathway is under debate, but we have found that SOCE takes place in cortical neurons, although contrary to findings in neuroblastoma cell lines, it is not modulated by Ca2+ uptake into mitochondria. Moreover, we have investigated the role of neuronal SOCE in the response to physiological stimuli which have the ability to mobilize Ca2+ from intracellular stores, and we found that SOCE is involved in both mAChRs and mGluRs function: a) SOCE plays a role in muscarinic-enhanced spontaneous Ca2+ oscillations and the subsequent stimulation of mitochondrial respiration; and b) SOCE is required for the response to the mGluRs I agonist DHPG, to maintain cytosolic Ca2+ and develop DHPG-LTD.