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Sci Signal. 2018 Jan 30;11(515). pii: eaal2039. doi: 10.1126/scisignal.aal2039.

Fluorescent Ca2+ indicators directly inhibit the Na,K-ATPase and disrupt cellular functions.

Author information

1
Center for Translational Neuromedicine, Departments of Neurosurgery and Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
2
Center for Neuroscience Research, Children's Research Institute, Children's National Health System, Washington, DC 20010, USA.
3
Center for Translational Neuromedicine, Departments of Neurosurgery and Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA. nedergaard@urmc.rochester.edu.

Abstract

Fluorescent Ca2+ indicators have been essential for the analysis of Ca2+ signaling events in various cell types. We showed that chemical Ca2+ indicators, but not a genetically encoded Ca2+ indicator, potently suppressed the activity of Na+- and K+-dependent adenosine triphosphatase (Na,K-ATPase), independently of their Ca2+ chelating activity. Loading of commonly used Ca2+ indicators, including Fluo-4 acetoxymethyl (AM), Rhod-2 AM, and Fura-2 AM, and of the Ca2+ chelator BAPTA AM into cultured mouse or human neurons, astrocytes, cardiomyocytes, or kidney proximal tubule epithelial cells suppressed Na,K-ATPase activity by 30 to 80%. Ca2+ indicators also suppressed the agonist-induced activation of the Na,K-ATPase, altered metabolic status, and caused a dose-dependent loss of cell viability. Loading of Ca2+ indicators into mice, which is carried out for two-photon imaging, markedly altered brain extracellular concentrations of K+ and ATP. These results suggest that a critical review of data obtained with chemical Ca2+ indicators may be necessary.

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