title: SPAK differentially mediates vasopressin effects on sodium cotransporters.
abstract: Activation of the Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2) and the Na(+)-Cl(-)-cotransporter (NCC) by vasopressin includes their phosphorylation at defined, conserved N-terminal threonine and serine residues, but the kinase pathways that mediate this action of vasopressin are not well understood. Two homologous Ste20-like kinases, SPS-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive kinase (OSR1), can phosphorylate the cotransporters directly. In this process, a full-length SPAK variant and OSR1 interact with a truncated SPAK variant, which has inhibitory effects. Here, we tested whether SPAK is an essential component of the vasopressin stimulatory pathway. We administered desmopressin, a V2 receptor-specific agonist, to wild-type mice, SPAK-deficient mice, and vasopressin-deficient rats. Desmopressin induced regulatory changes in SPAK variants, but not in OSR1 to the same degree, and activated NKCC2 and NCC. Furthermore, desmopressin modulated both the full-length and truncated SPAK variants to interact with and phosphorylate NKCC2, whereas only full-length SPAK promoted the activation of NCC. In summary, these results suggest that SPAK mediates the effect of vasopressin on sodium reabsorption along the distal nephron.
authors: Department of Anatomy, Charité Universitätsmedizin, Berlin, Germany.
authors: Turgay
authors: T
authors: Saritas
authors: Aljona
authors: A
authors: Borschewski
authors: James A
authors: JA
authors: McCormick
authors: Alexander
authors: A
authors: Paliege
authors: Christin
authors: C
authors: Dathe
authors: Shinichi
authors: S
authors: Uchida
authors: Andrew
authors: A
authors: Terker
authors: Nina
authors: N
authors: Himmerkus
authors: Markus
authors: M
authors: Bleich
authors: Sylvie
authors: S
authors: Demaretz
authors: Kamel
authors: K
authors: Laghmani
authors: Eric
authors: E
authors: Delpire
authors: David H
authors: DH
authors: Ellison
authors: Sebastian
authors: S
authors: Bachmann
authors: Kerim
authors: K
authors: Mutig
mesh_terms: D000818:Animals; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011910:Rats, Brattleboro; D017483:Receptors, Vasopressin / Q000819:agonists; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1
chemical_list: D017483:Receptors, Vasopressin; C578715:Slc12a1 protein, mouse; C578716:Slc12a1 protein, rat; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D011494:Protein Kinases; C486407:Stk39 protein, mouse; C116037:PAS domain kinases; C534421:OXSR1 protein, mouse; C506604:Oxsr1 protein, rat; D017346:Protein Serine-Threonine Kinases; D003894:Deamino Arginine Vasopressin
references: Physiol Rev. 2011 Jan;91(1):177-219
references: 21248166
references: Am J Physiol. 1978 Feb;234(2):F106-11
references: 623299
references: Exp Neurol. 2001 Oct;171(2):227-34
references: 11573975
references: J Biol Chem. 2003 Jul 18;278(29):26946-51
references: 12732642
references: Neuropeptides. 1993 Feb;24(2):105-8
references: 8459909
references: J Biol Chem. 2002 Dec 27;277(52):50812-9
references: 12386165
references: Am J Physiol Cell Physiol. 2010 Sep;299(3):C614-20
references: 20463172
references: J Cell Sci. 2008 Mar 1;121(Pt 5):675-84
references: 18270262
references: Am J Physiol Renal Physiol. 2007 Sep;293(3):F662-9
references: 17507603
references: Am J Physiol. 1990 Apr;258(4 Pt 2):F973-9
references: 2184677
references: J Am Soc Nephrol. 2008 Sep;19(9):1721-31
references: 18596120
references: J Cell Biol. 2007 Jan 1;176(1):89-100
references: 17190791
references: J Cell Sci. 2011 Mar 1;124(Pt 5):789-800
references: 21321328
references: Am J Physiol Renal Physiol. 2011 Dec;301(6):F1143-59
references: 21900458
references: Arch Biochem Biophys. 1998 Jul 15;355(2):233-40
references: 9675032
references: Am J Physiol Renal Physiol. 2007 Oct;293(4):F1166-77
references: 17626156
references: Mol Cell Biol. 2010 Jun;30(12):3027-37
references: 20385770
references: Pflugers Arch. 2010 Sep;460(4):695-702
references: 20490538
references: Histochem Cell Biol. 2011 Jul;136(1):25-35
references: 21660484
references: Physiol Rev. 2005 Apr;85(2):423-93
references: 15788703
references: J Biol Chem. 2003 Dec 26;278(52):52848-56
references: 14563843
references: Kidney Int. 2010 Jul;78(2):160-9
references: 20445498
references: Am J Physiol Renal Physiol. 2010 Mar;298(3):F502-9
references: 20007345
references: Am J Physiol Renal Physiol. 2008 Sep;295(3):F789-802
references: 18579701
references: J Cell Sci. 2008 Oct 15;121(Pt 20):3293-304
references: 18843116
references: Biochem J. 2005 Oct 1;391(Pt 1):17-24
references: 16083423
references: J Am Soc Nephrol. 2010 Nov;21(11):1868-77
references: 20813865
references: Nat Genet. 1996 Jun;13(2):183-8
references: 8640224
references: Kidney Int. 2011 Jan;79(1):66-76
references: 20720527
references: Nat Genet. 1996 Jan;12(1):24-30
references: 8528245
references: Cell Metab. 2011 Sep 7;14(3):352-64
references: 21907141
references: Domest Anim Endocrinol. 2004 Jul;27(1):1-12
references: 15158530
references: J Neurosci. 2012 Jan 11;32(2):593-8
references: 22238094
references: EMBO Mol Med. 2010 Feb;2(2):63-75
references: 20091762
references: Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17538-43
references: 21972418