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10.1073/pnas.0802966105 http://scihub22266oqcxt.onion/10.1073/pnas.0802966105 18550832!2448858!18550832     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Proc+Natl+Acad+Sci+U+S+A 2008 ; 105 (24): 8458-63 Nephropedia Template TP {{tp|p=18550832|t=2008. Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases |pdf=|usr=}}{{18550832}} gab.com Text Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=18550832 #FOAvip The Na(+):K(+):2Cl(-) cotransporter (NKCC2) is the target of loop diuretics and is mutated in Bartter's syndrome, a heterogeneous autosomal recessive disease that impairs salt reabsorption in the kidney's thick ascending limb (TAL). Despite the importance of this cation/chloride cotransporter (CCC), the mechanisms that underlie its regulation are largely unknown. Here, we show that intracellular chloride depletion in Xenopus laevis oocytes, achieved by either coexpression of the K-Cl cotransporter KCC2 or low-chloride hypotonic stress, activates NKCC2 by promoting the phosphorylation of three highly conserved threonines (96, 101, and 111) in the amino terminus. Elimination of these residues renders NKCC2 unresponsive to reductions of [Cl(-)](i). The chloride-sensitive activation of NKCC2 requires the interaction of two serine-threonine kinases, WNK3 (related to WNK1 and WNK4, genes mutated in a Mendelian form of hypertension) and SPAK (a Ste20-type kinase known to interact with and phosphorylate other CCCs). WNK3 is positioned upstream of SPAK and appears to be the chloride-sensitive kinase. Elimination of WNK3's unique SPAK-binding motif prevents its activation of NKCC2, as does the mutation of threonines 96, 101, and 111. A catalytically inactive WNK3 mutant also completely prevents NKCC2 activation by intracellular chloride depletion. Together these data reveal a chloride-sensing mechanism that regulates NKCC2 and provide insight into how increases in the level of intracellular chloride in TAL cells, as seen in certain pathological states, could drastically impair renal salt reabsorption. Twit Text FOAVip Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=18550832 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=18550832 #FOAvip English Wikipedia <ref>{{Cite pmid|18550832}}</ref> Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases #MMPMID18550832 Ponce-Coria J; San-Cristobal P; Kahle KT; Vazquez N; Pacheco-Alvarez D; de Los Heros P; Juarez P; Munoz E; Michel G; Bobadilla NA; Gimenez I; Lifton RP; Hebert SC; Gamba G Proc Natl Acad Sci U S A 2008[Jun]; 105 (24): 8458-63 PMID18550832show ga The Na(+):K(+):2Cl(-) cotransporter (NKCC2) is the target of loop diuretics and is mutated in Bartter's syndrome, a heterogeneous autosomal recessive disease that impairs salt reabsorption in the kidney's thick ascending limb (TAL). Despite the importance of this cation/chloride cotransporter (CCC), the mechanisms that underlie its regulation are largely unknown. Here, we show that intracellular chloride depletion in Xenopus laevis oocytes, achieved by either coexpression of the K-Cl cotransporter KCC2 or low-chloride hypotonic stress, activates NKCC2 by promoting the phosphorylation of three highly conserved threonines (96, 101, and 111) in the amino terminus. Elimination of these residues renders NKCC2 unresponsive to reductions of [Cl(-)](i). The chloride-sensitive activation of NKCC2 requires the interaction of two serine-threonine kinases, WNK3 (related to WNK1 and WNK4, genes mutated in a Mendelian form of hypertension) and SPAK (a Ste20-type kinase known to interact with and phosphorylate other CCCs). WNK3 is positioned upstream of SPAK and appears to be the chloride-sensitive kinase. Elimination of WNK3's unique SPAK-binding motif prevents its activation of NKCC2, as does the mutation of threonines 96, 101, and 111. A catalytically inactive WNK3 mutant also completely prevents NKCC2 activation by intracellular chloride depletion. Together these data reveal a chloride-sensing mechanism that regulates NKCC2 and provide insight into how increases in the level of intracellular chloride in TAL cells, as seen in certain pathological states, could drastically impair renal salt reabsorption. |Amino Acid Motifs[MESH] |Animals[MESH] |Cells, Cultured[MESH] |Chlorides/*metabolism[MESH] |Humans[MESH] |Mice[MESH] |Mutation[MESH] |Oocytes[MESH] |Phosphorylation[MESH] |Protein Serine-Threonine Kinases/*metabolism[MESH] |Rats[MESH] |Sodium-Potassium-Chloride Symporters/chemistry/genetics/*metabolism[MESH] |Solute Carrier Family 12, Member 1[MESH] |Threonine/chemistry/genetics/metabolism[MESH]Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3(epmc).pdf DeepDyve Pubget Overpricing