title: Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC.
abstract: Arginine vasopressin (AVP) affects kidney function via vasopressin V2 receptors that are linked to activation of adenylyl cyclase (AC) and an increase in cyclic adenosine monophosphate formation. AVP/cyclic adenosine monophosphate enhance the phosphorylation of the Na-K-2Cl cotransporter (NKCC2) at serine residue 126 (pS126 NKCC2) and of the Na-Cl cotransporter (NCC) at threonine 58 (pT58 NCC). The isoform(s) of AC involved in these responses, however, were unknown. Phosphorylation of S126 NKCC2 and T58 NCC, induced by the V2 receptor agonist (1-desamino-8-D-arginine vasopressin) in wild-type mice, is lacking in knockout mice for AC isoform 6 (AC6). With regard to NKCC2 phosphorylation, the stimulatory effect of 1-desamino-8-D-AVP and the defect in AC6(-/-) mice seem to be restricted to the medullary portion of the thick ascending limb. AC6 is also a stimulator of total renal NKCC2 protein abundance in medullary and cortical thick ascending limb. Consequently, mice lacking AC6 have lower NKCC2 expression and a mild Bartter syndrome-like phenotype, including lower plasma concentrations of K+ and H+ and compensatory upregulation of NCC. Increased AC6-independent phosphorylation of NKCC2 at S126 might help to stabilize NKCC2 activity in the absence of AC6. Renal AC6 determines total NKCC2 expression and mediates vasopressin-induced NKCC2/NCC phosphorylation. These regulatory mechanisms, which are defective in AC knockout mice, are likely responsible for the observed mild Bartter syndrome.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California 92161, USA. trieg@ucsd.edu
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uchida
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Robert A
authors.initials: RA
authors.lastname: Fenton
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D050034:Antidiuretic Agents / Q000494:pharmacology; D001477:Bartter Syndrome / Q000378:metabolism; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D049992:Sodium Chloride Symporters / Q000096:biosynthesis* / Q000235:genetics; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis* / Q000235:genetics; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins / Q000502:physiology; D014883:Water-Electrolyte Imbalance / Q000378:metabolism
chemical_list: D050034:Antidiuretic Agents; C578715:Slc12a1 protein, mouse; D049992:Sodium Chloride Symporters; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D003894:Deamino Arginine Vasopressin