International Journal of Molecular Sciences | |
STIM1 Deficiency Leads to Specific Down-Regulation of ITPR3 in SH-SY5Y Cells | |
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 ICRACcurrent, 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.
【 授权许可】
Unknown