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Cyclosporin binding to a protein component of the renal Na+-D-glucose cotransporter

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Fritzsch,  Günter
Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Koepsell,  Hermann
Department of Physiology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Ziegler, K., Frimmer, M., Fritzsch, G., & Koepsell, H. (1990). Cyclosporin binding to a protein component of the renal Na+-D-glucose cotransporter. The Journal of Biological Chemistry, 265(6), 3270-3277. doi:10.1016/S0021-9258(19)39763-7.


Cite as: http://hdl.handle.net/21.11116/0000-0007-9337-5
Abstract
The immunosuppressive and nephrotoxic agent cyclosporin binds to a renal polypeptide with an apparent molecular weight of 75,000 which has been identified as a component of the renal Na+-D-glucose cotransporter (Neeb, M., Kunz, U., and Koepsell, H. (1987) J. Biol. Chem. 262, 10718-10729). The same Mr 75,000 polypeptide was covalently labeled with the D-glucose analog 10-N-(bromoacetyl)amino-1-decyl-beta-D-glucopyranoside and with the cyclosporin analog N epsilon-(diazotrifluoroethyl)benzyl-D-Lys8- cyclosporin (CSDZ). CSDZ labeling was decreased when the brush-border membrane proteins were incubated with monoclonal antibodies against the Na+-D-glucose cotransporter. In the presence of 145 mM Na+, CSDZ labeling was decreased by D-glucose (1 microM, 1 mM, or 100 mM) and by phlorizin (100 or 500 microM). In the absence of Na+, CSDZ labeling was distinctly increased by 50 microM phlorizin and was slightly increased by 1 mM D-glucose, whereas CSDZ labeling was decreased by 50 microM phloretin and by 500 microM phlorizin. Furthermore, Na+-dependent high affinity phlorizin binding to the Na+-D-glucose cotransporter was competitively inhibited by cyclosporin A (Ki = 0.04 microM) while Na+-D-glucose cotransport was not influenced. The data suggest that a part of the cyclosporin binding domain on the Na+-D-glucose cotransporter is identical to the phloretin binding domain of the high affinity phlorizin binding site. While phloretin or the phloretin moiety of phlorizin may directly displace cyclosporin, interaction of D-glucose or of the D-glucose moiety of phlorizin with the transporter may alter the conformation of the cyclosporin binding site and this conformational change may be modulated by Na+.