Abstract
Transthyretin (TTR) is a functional protein in the pancreatic β-cell. It promotes insulin release and protects against β-cell death. We now demonstrate by ligand blotting, adsorption to specific magnetic beads, and surface plasmon resonance that TTR binds to glucose-regulated proteins (Grps)78, 94, and 170, which are members of the endoplasmic reticulum chaperone family, but Grps78 and 94 have also been found at the plasma membrane. The effect of TTR on changes in cytoplasmic free Ca2+ concentration ([Ca2+]i) was abolished if the cells were treated with either dynasore, a specific inhibitor of dynamin GTPase that blocks clathrin-mediated endocytosis, or an antibody against Grp78, that prevents TTR from binding to Grp78. The conclusion is that TTR binds to Grp78 at the plasma membrane, is internalized into the β-cell via a clathrin-dependent pathway, and that this internalization is necessary for the effects of TTR on β-cell function.
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Acknowledgments
We thank Prof Tomas Kirchhausen, Harvard Medical School, who kindly provided us with dynasore, synthesized by Dr Henry E Pelish. This work was supported by grants from The Family Erling-Persson Foundation, The Swedish Research Council, the Novo Nordisk Foundation, Swedish Diabetes Association, Barndiabetesfonden, Karolinska Institutet, Magnus Bergwalls Foundation, The Knut and Alice Wallenberg Foundation, the Skandia Insurance Company Ltd., VIBRANT (FP7-228933-2), Strategic Research Program in Diabetes at Karolinska Institutet and Berth von Kantzow’s Foundation.
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Dekki, N., Refai, E., Holmberg, R. et al. Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell. Cell. Mol. Life Sci. 69, 1733–1743 (2012). https://doi.org/10.1007/s00018-011-0899-8
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DOI: https://doi.org/10.1007/s00018-011-0899-8