title: Enhanced catecholamine release in mice expressing PKB/SGK-resistant GSK3.
abstract: Glycogen synthase kinase 3 (GSK3) plays a decisive role in the regulation of multiple functions. GSK3 is phosphorylated and its activity inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms, which are in turn activated by growth factors through phosphoinositide (PI) 3 kinase signaling. PI3/PKB/Akt/SGK-dependent inhibition of GSK3 is disrupted in gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK3α,ß (gsk3                         (                            KI                         )) where the serine of the PKB/SGK phosphorylation site has been replaced by alanine. Recent experiments revealed that blood pressure is significantly higher in those mice than in wild type mice (gsk3                         (                            WT                         )). The present study was performed to elucidate the underlying cause. Blood pressure was determined with the tail cuff method, heart rate by ECG measurements, catecholamine concentrations by ELISA, and vanillylmandelic acid by high pressure liquid chromatography. As a result, blood pressure and heart rate were significantly higher in gsk3                         (                            KI                         ) than in gsk3                         (                            WT                         ) mice. The α-adrenergic blocker prazosin (1 μg/g body weight, b.w.) and the ganglion blocker hexamethonium (40 μg/g b.w.) decreased blood pressure to a larger extent in gsk3                         (                            KI                         ) than in gsk3                         (                            WT                         ) mice and virtually abrogated the difference between genotypes. Similarly, the β-adrenergic blocker atenolol (5 μg/g b.w.) decreased the heart rate to a larger extent in gsk3                         (                            KI                         ) than in gsk3                         (                            WT                         ) mice and again dissipated the difference of heart rate between genotypes. Plasma epinephrine and norepinephrine concentrations, as well as urinary excretion of vanillylmandelic acid, were significantly higher in gsk3                         (                            KI                         ) than in gsk3                         (                            WT                         ) mice. The observations reveal a completely novel function of PKB/Akt/SGK-dependent GSK3 signaling, i.e., regulation of catecholamine release.
authors.affiliation: Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
authors.forename: Balasaheb
authors.initials: B
authors.lastname: Siraskar
authors.forename: Jakob
authors.initials: J
authors.lastname: Völkl
authors.forename: Mohamed Siyabeldin E
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Michael
authors.initials: M
authors.lastname: Hierlmeier
authors.forename: Shuchen
authors.initials: S
authors.lastname: Gu
authors.forename: Evi
authors.initials: E
authors.lastname: Schmid
authors.forename: Christina
authors.initials: C
authors.lastname: Leibrock
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Undine E
authors.initials: UE
authors.lastname: Lang
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D018738:Hexamethonium / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000959:Antihypertensive Agents; D001262:Atenolol; D002395:Catecholamines; D038362:Glycogen Synthase Kinase 3; D018738:Hexamethonium; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099184:Serum-Glucocorticoid Regulated Kinases