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cotransporter gene
encodes a furosemide-sensitive
Na+-Clcotransporter
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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