PMID:20056751

Citation	Rao, R, Patel, S, Hao, C, Woodgett, J and Harris, R (2010) GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity. J. Am. Soc. Nephrol. 21:428-37
Abstract	Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
Links	PubMed PMC2831860 Online version:10.1681/ASN.2009060672
Keywords	Adenylate Cyclase/genetics; Adenylate Cyclase/metabolism; Animals; Antidiuretic Agents/pharmacology; Aquaporin 2/genetics; Aquaporin 2/metabolism; Cells, Cultured; Cyclic AMP/metabolism; Deamino Arginine Vasopressin/pharmacology; Female; Forskolin/pharmacology; Glycogen Synthase Kinase 3/genetics; Glycogen Synthase Kinase 3/metabolism; Kidney Concentrating Ability/drug effects; Kidney Concentrating Ability/physiology; Kidney Tubules, Collecting/cytology; Kidney Tubules, Collecting/enzymology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger/metabolism; Water Deprivation/physiology; Water-Electrolyte Balance/drug effects; Water-Electrolyte Balance/physiology
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:GSK3B		GO:0004696: glycogen synthase kinase 3 activity	ECO:0000315:		F		Figure 2-GSK3β gene deletion reduced urine osmolality after water deprivation. Urine osmolality values of urine collected during 18 hours of water deprivation.	complete CACAO 5839
MOUSE:GSK3B		GO:0007188: adenylate cyclase-modulating G-protein coupled receptor signaling pathway	ECO:0000315:		P		Figure 2-GSK3β gene deletion reduced urine osmolality after water deprivation. Urine osmolality values of urine collected during 18 hours of water deprivation.	complete CACAO 6104

References

See Help:References for how to manage references in GONUTS.