Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

Silei Yang,Francesco Roselli,Alexandre V Patchev,Shuang Yu,Osborne F.X Almeida

doi:10.1074/jbc.m113.470146

Abstract

Despite numerous descriptions of rapid effects of corticosterone on neuronal function, the intracellular mechanisms responsible for these changes remain elusive. The present comprehensive analysis reveals that signaling from a membrane-located G protein-coupled receptor activates PKC, Akt/PKB, and PKA, which subsequently trigger the phosphorylation of the tyrosine kinases Pyk2, Src, and Abl. These changes induce rapid cytoskeletal rearrangements (increased PSD-95 co-clustering) within the post-synaptic density; these events are accompanied by increased surface NMDA receptor expression, reflecting corticosterone-induced inhibition of NMDA receptor endocytosis. Notably, none of these signaling mechanisms require de novo protein synthesis. The observed up-regulation of ERK1/2 (downstream of NMDA receptor signaling) together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors.

Highlights

The intracellular signaling cascades through which corticosterone rapidly alters neuronal activity are poorly defined
The observed up-regulation of ERK1/2 together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors
Corticosterone Activates the Src-family Kinase Signaling Pathway—tyrosine kinase (TK) are expressed in neurons and are enriched in synapses [21,22,23,24] where they phosphorylate and activate a range of substrates [25]

Summary

Background

The intracellular signaling cascades through which corticosterone rapidly alters neuronal activity are poorly defined. These changes induce rapid cytoskeletal rearrangements (increased PSD-95 co-clustering) within the post-synaptic density; these events are accompanied by increased surface NMDA receptor expression, reflecting corticosterone-induced inhibition of NMDA receptor endocytosis None of these signaling mechanisms require de novo protein synthesis. The observed up-regulation of ERK1/2 (downstream of NMDA receptor signaling) together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors. The adaptations triggered by GC secretion are considered to result from activation of glucocorticoid (GR) and/or miner-

Present address

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION