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

International Journal of Molecular Sciences

Carlos Pascual-Caro¹  Yolanda Orantos-Aguilera¹  FranciscoJavier Martin-Romero¹  Irene Sanchez-Lopez¹  Eulalia Pozo-Guisado²  JanB. Parys³  Estela Area-Gomez⁴  Jaime de Juan-Sanz⁵ 

[1] Department of Biochemistry and Molecular Biology, School of Life Sciences and Institute of Molecular Pathology and Biomarkers, University of Extremadura, 06006 Badajoz, Spain;Department of Cell Biology, School of Medicine and Institute of Molecular Pathology and Biomarkers, University of Extremadura, 06006 Badajoz, Spain;Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, KU Leuven, B-3000 Leuven, Belgium;Department of Neurology, Columbia University Medical Center, New York, 10032-3748 NY, USA;Sorbonne Universités and Institut du Cerveau et de la Moelle Epinière (ICM) - Hôpital Pitié-Salpêtrière, Inserm, CNRS, 75013 Paris, France;

关键词: Calcium;    endoplasmic reticulum;    IP3 receptor;    mitochondria;    neurodegeneration;    STIM1;   

DOI  :  10.3390/ijms21186598

来源: DOAJ

【 摘 要 】

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 I_CRACcurrent, whereas the binding with the voltage-operated Ca²⁺ channel Ca_V1.2 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.

【 授权许可】

Unknown