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The functional role of the second npxy motif of the lrp1 beta-chain in tissue-type plasminogen activator-mediated activation of N-methyl-d-aspartate receptors

Journal of biological chemistry. Bd. 283. H. 18. Bethesda, Md.: ASBMB 2008 S. 12004 - 12013

Erscheinungsjahr: 2008

ISBN/ISSN: 0021-9258

Publikationstyp: Zeitschriftenaufsatz

Sprache: Englisch

Doi/URN: 10.1074/jbc.M707607200

Volltext über DOI/URN

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Inhaltszusammenfassung


The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion ...The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the N-methyl-D-aspartate (NMDA) receptor. However, here we set out to examine whether LRP1 and the NMDA receptor might eventually act in a combined fashion to mediate tPA downstream signaling. By blocking tPA from binding to LRP1 using the receptor-associated protein, we were able to completely inhibit NMDA receptor activation. Additionally, inhibition of NMDA receptor calcium influx with MK-801 resulted in dramatic reduction of tPA-mediated downstream signaling. This indicates a functional interaction between the two receptors, since both experimental approaches resulted in strongly reduced calcium influx and Erk1/2 phosphorylation. Additionally, we were able to inhibit Erk1/2 activation by competing for the LRP1 C-terminal binding motif with a truncated PSD95 construct resembling its PDZ III domain. Furthermore, we identified the distal NPXY amino acid motif in the C terminus of LRP1 as the crucial element for LRP1-NMDA receptor interaction via the adaptor protein PSD95. These results provide new insights into the mechanism of a tPA-induced, LRP1-mediated gating mechanism for NMDA receptors.» weiterlesen» einklappen

Autoren


Martin, Anne M. (Autor)
Kuhlmann, Christoph (Autor)
Trossbach, Svenja (Autor)
Jaeger, Sebastian (Autor)
Waldron, Elaine (Autor)
Roebroek, Anton (Autor)
Luhmann, Heiko J. (Autor)
Laatsch, Alexander (Autor)
Weggen, Sascha (Autor)
Lessmann, Volkmar (Autor)
Pietrzik, Claus (Autor)

Klassifikation


DDC Sachgruppe:
Medizin