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Am J Physiol Renal Physiol 280: F574-F582, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 4, F574-F582, April 2001

Alternatively spliced isoform of apical Na+-K+-Clminus cotransporter gene encodes a furosemide-sensitive Na+-Clminus cotransporter

Consuelo Plata1, Patricia Meade1, Amy Hall2, Rick C. Welch3, Norma Vázquez1, Steven C. Hebert2, and Gerardo Gamba1

1 Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City CP 14000, Mexico; 2 Department of Cellular and Molecular Physiology, Yale University Medical School, New Haven, Connecticut 06520; and 3 Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232

In the absence of vasopressin, medullary thick ascending limb cells express a K+-independent, furosemide-sensitive Na+-Cl- cotransporter that is inhibited by hypertonicity. The murine renal specific Na+-K+-2 Cl- cotransporter gene (SLC12A1) gives rise to six alternatively spliced isoforms. Three feature a long COOH-terminal domain that encodes the butmetanide-sensitive Na+-K+-2 Cl- cotransporter (BSC1-9/NKCC2), and three with a short COOH-terminal domain, known as mBSC1-A4, B4, or F4 (19). Here we have determined the functional characteristics of mBSC1-A4, as expressed in Xenopus laevis oocytes. When incubated at normal oocyte osmolarity (~200 mosmol/kgH2O), mBSC1-4-injected oocytes do not express significant Na+ uptake over H2O-injected controls, and immunohistochemical analysis shows that the majority of mBSC1-4 protein is in the oocyte cytoplasm and not at the plasma membrane. In contrast, when mBSC1-4 oocytes are exposed to hypotonicity (~100 mosmol/kgH2O), a significant increase in Na+ uptake but not in 86Rb+ uptake is observed. The increased Na+ uptake is Cl- dependent, furosemide sensitive, and cAMP sensitive but K+ independent. Sodium uptake increases with decreasing osmolarity between 120 and 70 mosmol/kgH2O (r = 0.95, P < 0.01). Immunohistochemical analysis shows that in hypotonic conditions mBSC1-A4 protein is expressed in the plasma membrane. These studies indicate that the mBSC1-A4 isoform of the SLC12A1 gene encodes a hypotonically activated, cAMP- and furosemide-sensitive Na+-Cl- cotransporter. Thus it is possible that alternative splicing of the BSC1 gene could provide the molecular mechanism enabling the Na+-Cl--to-Na+-K+-2Cl- switching in thick ascending limb cells.

bumetanide; protein kinase A; adenosine 3',5'-cyclic monophosphate; thick ascending limb of Henle


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