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Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low‐density lipoprotein receptor family
Author(s) -
Ambjørn Malene,
Asmussen Johanne W.,
Lindstam Mats,
Gotfryd Kamil,
Jacobsen Christian,
Kiselyov Vladislav V.,
Moestrup Søren K.,
Penkowa Milena,
Bock Elisabeth,
Berezin Vladimir
Publication year - 2008
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.1471-4159.2007.05036.x
Subject(s) - neurite , receptor , microbiology and biotechnology , ldl receptor , signal transduction , biology , lipoprotein , biochemistry , in vitro , cholesterol
Accumulating evidence suggests that metallothionein (MT)‐I and ‐II promote neuronal survival and regeneration in vivo . The present study investigated the molecular mechanisms underlying the differentiation and survival‐promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor‐related protein‐1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor‐associated protein‐1, an antagonist of the low‐density lipoprotein receptor family, which also inhibited MT‐ and EmtinB‐induced neurite outgrowth and survival. MT‐mediated neurite outgrowth was furthermore inhibited by an anti‐megalin serum. EmtinB‐mediated inhibition of apoptosis occurred without a reduction of caspase‐3 activity, but was associated with reduced expression of the pro‐apoptotic B‐cell leukemia/lymphoma‐2 interacting member of cell death (Bim S ). Finally, evidence is provided that MT and EmtinB activate extracellular signal‐regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low‐density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.