Glucocorticoid adrenal steroids and glucocorticoid-inducible kinase isoforms in the regulation of GluR6 expression.
Generation of memory is enhanced during stress, an effect attributed to stimulation of neuronal learning by adrenal glucocorticoids. The glucocorticoid-dependent genes include the serum- and glucocorticoid-inducible kinase SGK1. SGK1 is activated through the phosphatidylinositol 3 kinase (PI3-kinase) pathway by growth factors such as insulin-like growth factor-1 (IGF1) or tumour growth factor beta (TGF-beta). Previously, a fourfold higher expression of SGK1 has been observed in fast-learning rats as compared with slow-learning rats. The mechanisms linking glucocorticoids or SGK1 with neuronal function have, however, remained elusive. We show here that treatment of mice with the glucocorticoid dexamethasone (238 microg day-1 for 8-20 days) enhances hippocampal expression of GluR6. Immunohistochemistry reveals significantly enhanced GluR6 protein abundance at neurones but not at astrocytes in mice. Immunohistochemistry and patch clamp on hippocampal neurones in primary culture reveal upregulation of GluR6 protein abundance and kainate-induced currents following treatment with dexamethasone (1 microm) and TGF-beta (1 microm). In Xenopus oocytes expressing rat GluR6, coexpression of SGK1 strongly increases glutamate-induced current at least partially by increasing the abundance of GluR6 protein in the plasma membrane. The related kinases SGK2 and SGK3 similarly stimulate GluR6, but are less effective than SGK1. The observations point to a novel mechanism regulating GluR6 which contributes to the regulation of neuronal function by glucocorticoids.
Strutz-Seebohm
Nathalie
N
Department of Physiology I, University of Tuebingen, 72076 Tuebingen, Germany.
Seebohm
Guiscard
G
Shumilina
Ekaterina
E
Mack
Andreas F
AF
Wagner
Hans-Joachim
HJ
Lampert
Angelika
A
Grahammer
Florian
F
Henke
Guido
G
Just
Lothar
L
Skutella
Thomas
T
Hollmann
Michael
M
Lang
Florian
F
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000196:embryology; D017874:Immediate-Early Proteins; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014982:Xenopus laevis; D000097806:GluK2 Kainate Receptor; D000099184:Serum-Glucocorticoid Regulated Kinases
D003907:Dexamethasone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; D000099184:Serum-Glucocorticoid Regulated Kinases