Journal
JOURNAL OF NEUROCHEMISTRY
Volume 119, Issue 3, Pages 447-459Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07423.x
Keywords
Coffin-Lowry syndrome; CREB; ERK; hippocampus; IEG; RSK2
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Funding
- French National Agency for Research [08-MNPS-021-01]
- Fondation Jerome Lejeune
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche
- College de France
- University of Strasbourg
- Ministere pour la Recherche et Technologie (France)
- Association Xtraordinaire (France)
- Higher Education Commission (HUG) of Pakistan
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Coffin-Lowry syndrome is a syndromic form of mental retardation caused by mutations of the Rps6ka3 gene encoding ribosomal s6 kinase (RSK)2. RSK2 belongs to a family containing four members in mammals: RSK1-4. RSKs are serine/threonine kinases and cytosolic substrates of extracellular signal-regulated kinase (ERK) in the Ras/MAPK signaling pathway. RSK2 is highly expressed in the hippocampus, and mrsk2_KO mice display spatial learning and memory impairment. In the present study, we provide evidence of abnormally increased phosphorylation of ERK1/2 in the hippocampus of mrsk2_KO mice. Further studies based on cultured hippocampal neurons revealed that glutamate activates ERK1/2 and RSKs, and confirmed a stronger activation of ERK1/2 in mrsk2_KO neurons that in WT cells. We, thus, provide further evidence that RSK2 exerts a feedback inhibitory effect on the ERK1/2 pathway. We also observed a transient sequestration of P-ERK1/2 in the cytoplasm upon glutamate stimulation. In addition, the transcription factors cAMP response element deficient neurons. Finally, c-Fos, Zif268 and Are were significantly over-expressed in mrsk2_KO neurons upon glutamate stimulation. Importantly, the increased phosphorylation of other RSK family members observed in mutant neurons was unable to compensate for RSK-2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunciton in mrsk2_KO mice and in the Coffin-Lowry syndrome.
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