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Vol. 15, Issue 3, 1044-1054, March 2004

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Cardiac Steroids Induce Changes in Recycling of the Plasma Membrane in Human NT2 Cells

Haim Rosen ^* , Vladimir Glukhman ^*, Tomer Feldmann ^*, Eleonora Fridman ^*, and David Lichtstein  

^* The Kuvin Center for the Study of Infectious and Tropical Diseases, Institute of Microbiology; Department of Physiology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

Submitted June 12, 2003; Revised November 9, 2003; Accepted November 21, 2003
Monitoring Editor: Keith Mostov

Cardiac steroids (CSs) are specific inhibitors of Na⁺, K⁺-ATPase activity. Although the presence of CS-like compounds in animal tissues has been established, their physiological role is not evident. In the present study, treatment of human NT2 cells with physiological concentrations (nanomolar) of CSs caused the accumulation of large vesicles adjacent to the nucleus. Experiments using N-(3-triethylammonium propyl)-4-(dibutilamino)styryl-pyrodinum dibromide, transferrin, low-density lipoprotein, and selected anti-transferrin receptor and Rab protein antibodies revealed that CSs induced changes in endocytosis-dependent membrane traffic. Our data indicate that the CS-induced accumulation of cytoplasmic membrane components is a result of inhibited recycling within the late endocytic pathway. Furthermore, our results support the notion that the CS-induced changes in membrane traffic is mediated by the Na⁺, K⁺-ATPase. These phenomena were apparent in NT2 cells at nanomolar concentrations of CSs and were observed also in other human cell lines, pointing to the generality of this phenomenon. Based on these observations, we propose that the endogenous CS-like compounds are physiological regulators of recycling of endocytosed membrane proteins and cargo.

Abbreviations used: CS, cardiac steroid; FM1-43, N-(3-triethylammonium propyl)-4-(dibutilamino)styryl-pyrodinum dibromide; LDL, low-density lipoproteins; TfR, transferrin receptor.

Correspondingauthors. E-mail: hrose{at}md2.huji.ac.ilordavid@md2.huji.ac.il.

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