STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells.

Carlos Pascual-Caro, Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Jaime de Juan-Sanz, Jan B Parys, Estela Area-Gomez, Eulalia Pozo-Guisado, Francisco Javier Martin-Romero

International journal of molecular sciences 2020 Sep 09

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STIM1 is an endoplasmic reticulum (ER) protein that modulates the activity of a number of Ca2+ transport systems. By direct physical interaction with ORAI1, a plasma membrane Ca2+ channel, STIM1 activates the ICRAC current, whereas the binding with the voltage-operated Ca2+ channel CaV1.2 inhibits the current through this latter channel. In this way, STIM1 is a key regulator of Ca2+ signaling in excitable and non-excitable cells, and altered STIM1 levels have been reported to underlie several pathologies, including immunodeficiency, neurodegenerative diseases, and cancer. In both sporadic and familial Alzheimer's disease, a decrease of STIM1 protein levels accounts for the alteration of Ca2+ handling that compromises neuronal cell viability. Using SH-SY5Y cells edited by CRISPR/Cas9 to knockout STIM1 gene expression, this work evaluated the molecular mechanisms underlying the cell death triggered by the deficiency of STIM1, demonstrating that STIM1 is a positive regulator of ITPR3 gene expression. ITPR3 (or IP3R3) is a Ca2+ channel enriched at ER-mitochondria contact sites where it provides Ca2+ for transport into the mitochondria. Thus, STIM1 deficiency leads to a strong reduction of ITPR3 transcript and ITPR3 protein levels, a consequent decrease of the mitochondria free Ca2+ concentration ([Ca2+]mit), reduction of mitochondrial oxygen consumption rate, and decrease in ATP synthesis rate. All these values were normalized by ectopic expression of ITPR3 in STIM1-KO cells, providing strong evidence for a new mode of regulation of [Ca2+]mit mediated by the STIM1-ITPR3 axis.

Citation

Carlos Pascual-Caro, Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Jaime de Juan-Sanz, Jan B Parys, Estela Area-Gomez, Eulalia Pozo-Guisado, Francisco Javier Martin-Romero. STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells. International journal of molecular sciences. 2020 Sep 09;21(18)