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1 Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Tlalpan, MexicoCity, Mexico
2 Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Tlalpan, MexicoCity, Mexico; Instituto Nacional de Cienicas Medicas y Nutricion Salvador Zubiran, Tlalpan, Mexico City, Mexico
* To whom correspondence should be addressed. E-mail: gamba{at}sni.conacyt.mx.
The mammalian kidney bumetanide-sensitive Na+:K+:2Cl- and thiazide-sensitive Na+:Cl- cotransporters are the major pathways for salt reabsorption in the thick ascending limb of Henle's loop and distal convoluted tubule, respectively. These cotransporters serve as receptors for the loop and thiazide type diuretics and inactivating mutations of corresponding genes are associated with development of Bartter's syndrome type I and Gitleman's disease, respectively. Structural requirements for ion translocation and diuretic binding specificity are unknown. As an initial approach for analyzing structural determinants conferring ion or diuretic preferences in these cotransporters, we exploited functional differences and structural similarities between Na+:K+:2Cl- and Na+:Cl- cotransporters, to design and study chimeric proteins in which the Nterminal and/or C-terminal domains were switched between each other. Thus, six chimeric proteins were produced. Using the heterologous expression system of Xenopus laevis oocytes we observed that four chimeras exhibited functional activity. Our results revealed that in the Na+:K+:2Cl- cotransporter ion translocation and diuretic binding specificity is determined by the central hydrophobic domain. Thus, N-terminal and C-terminal domains do not play a role in defining these properties. A similar conclusion can be suggested for the Na+:Cl- cotransporter.
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  G. Gamba The thiazide-sensitive Na+-Cl- cotransporter: molecular biology, functional properties, and regulation by WNKs Am J Physiol Renal Physiol, October 1, 2009; 297(4): F838 - F848. [Abstract] [Full Text] [PDF]
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A. Paredes, C. Plata, M. Rivera, E. Moreno, N. Vazquez, R. Munoz-Clares, S. C. Hebert, and G. Gamba Activity of the renal Na+-K+-2Cl- cotransporter is reduced by mutagenesis of N-glycosylation sites: role for protein surface charge in Cl- transport Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1094 - F1102. [Abstract] [Full Text] [PDF]
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