N. Strutz-Seebohm, G. Seebohm, E. Shumilina, A.F. Mack, H.-J. Wagner, A. Lampert, F. Grahammer, G. Henke, L. Just, T. Skutella, M. Hollmann, and F. Lang (2005).
Glucocorticoid adrenal steroids and glucocorticoid-inducible kinase isoforms in the regulation of GluR6 expression.
Journal of Physiology 565(Pt 2): 391-401.
doi: 10.1113/jphysiol.2004.079624
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 PI3 kinase pathway by growth factors such as IGF1 or TGF-β. Previously, a 4-fold higher expression of SGK1 has been observed in fast learning rats as compared to slowly learning rats. The mechanisms linking glucocorticoids or SGK1 with neuronal function have, however, remained elusive. We show here that treatment of wild type mice with the glucocorticoid dexamethasone (238 µg/day for 8-20 days) enhances hippocampal expression of GluR6. Immunohistochemistry reveals significantly enhanced GluR6 protein abundance at neurons but not at astrocytes in mice. Immunohistochemistry and patch clamp on hippocampal neurons in primary culture reveals upregulation of GluR6 protein abundance and kainate-induced currents following treatment with dexamethasone (1 µM) and TGF-β (1 µM). 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.