Article Dans Une Revue International Journal of Molecular Sciences Année : 2020

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

Résumé

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.
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Dates et versions

hal-02989684 , version 1 (05-11-2020)

Identifiants

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Carlos Pascual-Caro, Yolanda Orantos-Aguilera, Irene Sanchez-Lopez, Jaime de Juan-Sanz, Jan B Parys, et al.. STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells. International Journal of Molecular Sciences, 2020, 21 (18), pp.6598. ⟨10.3390/ijms21186598⟩. ⟨hal-02989684⟩
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