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10.1093/hmg/ddv185 http://scihub22266oqcxt.onion/10.1093/hmg/ddv185 25994507!4512625!25994507     free     free     free Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 209.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Hum+Mol+Genet 2015 ; 24 (16): 4545-58 Nephropedia Template TP {{tp|p=25994507|t=2015. Critical role of the SPAK protein kinase CCT domain in controlling blood pressure |pdf=|usr=}}{{25994507}} gab.com Text Critical role of the SPAK protein kinase CCT domain in controlling blood pressure JO: Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=25994507 #FOAvip The STE20/SPS1-related proline/alanine-rich kinase (SPAK) controls blood pressure (BP) by phosphorylating and stimulating the Na-Cl (NCC) and Na-K-2Cl (NKCC2) co-transporters, which regulate salt reabsorption in the kidney. SPAK possesses a conserved carboxy-terminal (CCT) domain, which recognises RFXV/I motifs present in its upstream activator [isoforms of the With-No-lysine (K) kinases (WNKs)] as well as its substrates (NCC and NKCC2). To define the physiological importance of the CCT domain, we generated knock-in mice in which the critical CCT domain Leu502 residue required for high affinity recognition of the RFXI/V motif was mutated to Alanine. The SPAK CCT domain defective knock-in animals are viable, and the Leu502Ala mutation abolished co-immunoprecipitation of SPAK with WNK1, NCC and NKCC2. The CCT domain defective animals displayed markedly reduced SPAK activity and phosphorylation of NCC and NKCC2 co-transporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in mRNA levels. The SPAK CCT domain knock-in mice showed typical features of Gitelman Syndrome with mild hypokalaemia, hypomagnesaemia, hypocalciuria and displayed salt wasting on switching to a low-Na diet. These observations establish that the CCT domain plays a crucial role in controlling SPAK activity and BP. Our results indicate that CCT domain inhibitors would be effective at reducing BP by lowering phosphorylation as well as expression of NCC and NKCC2. Twit Text FOAVip Critical role of the SPAK protein kinase CCT domain in controlling blood pressure ????Hum Mol Genet http://www.kidney.de/pget.php?&tw=1&pmid=25994507 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25994507 #FOAvip English Wikipedia <ref>{{Cite pmid|25994507}}</ref> Critical role of the SPAK protein kinase CCT domain in controlling blood pressure #MMPMID25994507 Zhang J; Siew K; Macartney T; O'Shaughnessy KM; Alessi DR Hum Mol Genet 2015[Aug]; 24 (16): 4545-58 PMID25994507show ga The STE20/SPS1-related proline/alanine-rich kinase (SPAK) controls blood pressure (BP) by phosphorylating and stimulating the Na-Cl (NCC) and Na-K-2Cl (NKCC2) co-transporters, which regulate salt reabsorption in the kidney. SPAK possesses a conserved carboxy-terminal (CCT) domain, which recognises RFXV/I motifs present in its upstream activator [isoforms of the With-No-lysine (K) kinases (WNKs)] as well as its substrates (NCC and NKCC2). To define the physiological importance of the CCT domain, we generated knock-in mice in which the critical CCT domain Leu502 residue required for high affinity recognition of the RFXI/V motif was mutated to Alanine. The SPAK CCT domain defective knock-in animals are viable, and the Leu502Ala mutation abolished co-immunoprecipitation of SPAK with WNK1, NCC and NKCC2. The CCT domain defective animals displayed markedly reduced SPAK activity and phosphorylation of NCC and NKCC2 co-transporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in mRNA levels. The SPAK CCT domain knock-in mice showed typical features of Gitelman Syndrome with mild hypokalaemia, hypomagnesaemia, hypocalciuria and displayed salt wasting on switching to a low-Na diet. These observations establish that the CCT domain plays a crucial role in controlling SPAK activity and BP. Our results indicate that CCT domain inhibitors would be effective at reducing BP by lowering phosphorylation as well as expression of NCC and NKCC2. |*Blood Pressure[MESH] |*Mutation, Missense[MESH] |Amino Acid Substitution[MESH] |Animals[MESH] |Gitelman Syndrome/genetics/*metabolism/physiopathology[MESH] |HEK293 Cells[MESH] |Humans[MESH] |Mice[MESH] |Mice, Mutant Strains[MESH] |Phosphorylation/genetics[MESH] |Protein Serine-Threonine Kinases/genetics/*metabolism[MESH] |Protein Structure, Tertiary[MESH]Critical role of the SPAK protein kinase CCT domain in controlling blo(epmc).pdf DeepDyve Pubget Overpricing