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Altered ERK/MAPK signaling in the hippocampus of the mrsk2_KO mouse model of Coffin‐Lowry syndrome
Author(s) -
Schneider Anne,
Mehmood Tahir,
Pannetier Solange,
Hanauer André
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07423.x
Subject(s) - mapk/erk pathway , glutamate receptor , kinase , phosphorylation , hippocampal formation , biology , ribosomal s6 kinase , hippocampus , microbiology and biotechnology , stimulation , signal transduction , serine , neuroscience , endocrinology , biochemistry , protein kinase b , receptor , p70 s6 kinase 1
J. Neurochem. (2011) 119 , 447–459. Abstract 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 than 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 binding and Ets LiKe gene1 show over‐activation in RSK2‐deficient neurons. Finally, c‐Fos , Zif268 and Arc 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 RSK2 deficiency. This aberrant ERK1/2 signaling can influence various neuronal functions, and thus play a significant role in cognitive dysfunction in mrsk2_KO mice and in the Coffin‐Lowry syndrome.