Molecular mechanisms and regulation of furosemide-sensitive Na-K-Cl cotransporters.

PURPOSE OF REVIEW: Relevant advances towards understanding how furosemide-sensitive Na-K-Cl cotransporters (NKCC) are regulated by alternative splicing, phosphorylation and membrane expression have been made, which are critical to comprehending the role of NKCCs in blood pressure homeostasis. RECENT
FINDINGS: A major breakthrough has been the description of a macromolecular complex responsible for the regulatory phosphorylation of NKCCs, involving members of two families of novel serine-threonine kinases: WNK kinases and Ste-20-related kinases SPAK and OSR1. A new regulatory pathway has been defined, with WNK lying upstream of SPAK-OSR1 and the latter kinases directly phosphorylating NKCC. New evidence has arisen supporting regulation of NKCC membrane expression, possibly through the same mechanisms regulating phosphorylation. Alternative splicing of kidney-specific NKCC2 also appears to be a regulated process. Renal roles for NKCC1 have been described, including an unexpected role in controlling renin secretion.
SUMMARY: We now begin to understand the biochemical pathways mediating NKCC regulatory phosphorylation, which are governed by kinases that, like NKCCs, have been linked to the genesis of hypertension. Complementary long-term regulation of NKCC membrane expression, alternative splicing or gene transcription, however, should not be overlooked. Deciphering the relationships between these processes will enhance our understanding of the pathogenesis of hypertension.