Journal
CELLULAR SIGNALLING
Volume 20, Issue 10, Pages 1715-1724Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2008.05.001
Keywords
A-kinase anchoring protein; cyclic adenosine monophosphate; potein kinase B/Akt; cAMP-dependent protein kinase; exchange proteins directly activated by cAMP; neuron; AKAP150; HT-4
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Funding
- University of Groningen
- Deutsche Forschungsgemeinschaft
- Dutch Brain Foundation
- European Union's FP6 [LSHM-CT-2005-018637]
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In diverse neuronal processes ranging from neuronal survival to synaptic plasticity cyclic adenosine monophosphate (cAMP)-dependent signaling is tightly connected with the protein kinase B (PKB)/Akt pathway but the precise nature of this connection remains unknown. In the current study we investigated the effect of two mainstream pathways initiated by cAMP, cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epac1 and Epac2) on PKB/Akt phosphorylation in primary cortical neurons and HT-4 cells. We demonstrate that PKA activation leads to a reduction of PKB/Akt phosphorylation, whereas activation of Epac has the opposite effect. This effect of Epac on PKB/Akt phosphorylation was mediated by Rap activation. The increase in PKB/Akt phosphorylation after Epac activation could be blocked by pretreatment with Epac2 siRNA and to a somewhat smaller extent by Epac1 siRNA. PKA, PKB/Akt and Epac were all shown to establish complexes with neuronal A-kinase anchoring protein150 (AKAP150). Interestingly, activation of Epac increased phosphorylation of PKB/Akt complexed to AKAP150. From experiments using PKA-binding deficient AKAP150 and peptides disrupting PKA anchoring to AKAPs, we conclude that AKAP150 acts as a key regulator in the two cAMP pathways to control PKB/Akt phosphorylation. (C) 2008 Elsevier Inc. All rights reserved.
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