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1 Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: eric.delpire{at}vanderbilt.edu.
The present study demonstrates functional interaction between SPAK (Ste20-related Proline Alanine rich Kinase), WNK4 (With No lysine(K)) and the widely expressed Na-K-2Cl cotransporter (NKCC1). NKCC1 function, measured in Xenopus laevis oocytes under both isosmotic (basal) or hyperosmotic (stimulated) conditions is unaffected when SPAK and WNK4 are expressed alone. In contrast, expression of both kinases with NKCC1 results in a significant increase in cotransporter activity and an insensitivity to external osmolarity or cell volume. NKCC1 activation is dependent on the catalytic activity of SPAK and likely of WNK4, as mutations in their catalytic domains result in an absence of cotransporter stimulation. Yeast two-hybrid experiments suggest that WNK4 does not interact directly with NKCC1, but interacts with SPAK. Functional experiments demonstrate that the binding of SPAK to WNK4 is also required, as a SPAK interacting-deficient WNK4 mutant (Phe997Ala) does not increase NKCC1 activity. We also show that the transport function of KCC2, a neuronal-specific K-Cl cotransporter, is diminished by the expression of both kinases under both isosmotic and hypoosmotic conditions. Our data are consistent with WNK4 interacting with SPAK which, in turn, phosphorylates and activates NKCC1, and phosphorylates and de-activates KCC2.
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