Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2008
MKP-1 inhibits high NaCl-induced activation of p38 but does not inhibit the activation of TonEBP/OREBP: opposite roles of p38alpha and p38delta.
High NaCl rapidly activates p38 MAPK by phosphorylating it, the phosphorylation presumably being regulated by a balance of kinases and phosphatases. Kinases are known, but the phosphatases are uncertain. Our initial purpose was to identify the phosphatases. ⋯ We conclude that high NaCl inhibits MKP-1, which contributes to the activation of p38. However, opposing actions of p38alpha and p38delta negate any effect on TonEBP/OREBP activity. Thus, activation of p38 isoforms by hypertonicity does not contribute to activation of TonEBP/OREBP because of opposing effects of p38alpha and p38delta, and effects of inhibitors of p38 depend on which isoform is affected, which can be misleading.
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2008
Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice.
beta-Site APP-cleaving enzyme 1 (BACE1) is required for the penultimate cleavage of the amyloid-beta precursor protein (APP) leading to the generation of amyloid-beta peptides that is central to the pathogenesis of Alzheimer's disease. In addition to its role in endoproteolysis of APP, BACE1 participates in the proteolytic processing of neuregulin 1 (NRG1) and influences the myelination of central and peripheral axons. Although NRG1 has been genetically linked to schizophrenia and NRG1(+/-) mice exhibit a number of schizophrenia-like behavioral traits, it is not known whether altered BACE1-dependent NRG1 signaling can cause similar behavioral abnormalities. ⋯ Moreover, although the total amount of ErbB4, a receptor for NRG1 was not changed, binding of ErbB4 with postsynaptic density protein 95 (PSD95) was significantly reduced in the brains of BACE1(-/-) mice. Consistent with the role of ErbB4 in spine morphology and synaptic function, BACE1(-/-) mice displayed reduced spine density in hippocampal pyramidal neurons. Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders.