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Anesthesiology Research Division, Laboratories of Cellular and Molecular Physiology, Departments of Anesthesiology and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232
K-Cl cotransporters (KCC) play
fundamental roles in ionic and osmotic homeostasis. To date, four
mammalian KCC genes have been identified. KCC2 is expressed exclusively
in neurons. Injection of Xenopus oocytes with KCC2
cRNA induced a 20-fold increase in Cl
-dependent,
furosemide-sensitive K+ uptake. Oocyte swelling increased
KCC2 activity 2-3 fold. A canonical tyrosine phosphorylation
site is located in the carboxy termini of KCC2 (R1081-Y1087) and
KCC4, but not in other KCC isoforms. Pharmacological studies, however,
revealed no regulatory role for phosphorylation of KCC2 tyrosine
residues. Replacement of Y1087 with aspartate or arginine dramatically
reduced K+ uptake under isotonic and hypotonic conditions.
Normal or near-normal cotransporter activity was observed when Y1087
was mutated to phenylalanine, alanine, or isoleucine. A tyrosine
residue equivalent to Y1087 is conserved in all identified KCCs from
nematodes to humans. Mutation of the Y1087 congener in KCC1 to
aspartate also dramatically inhibited cotransporter activity. Taken
together, these results suggest that replacement of Y1087 and its
congeners with charged residues disrupts the conformational state of
the carboxy terminus. We postulate that the carboxy terminus plays an
essential role in maintaining the functional conformation of KCC
cotransporters and/or is involved in essential regulatory protein-protein interactions.
neurons; potassium transport; cation-coupled chloride cotransport; cell volume regulation; furosemide
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