Here's an SFN calpain related paper from Dr. Baudry. In this study, the high impact CX-614 was found to upregulate AMPA receptors in the first 4 hours, but then decrease the number of AMPA receptors at 8 hours. The downregulation process was mediated by calpain, and involved the degradation of AMPA receptor interacting proteins -
>>> Program#/Poster#: 232.12/D19
Title: Internalization of AMPA receptors (AMPArs) induced by positive modulators of AMPArs: Roles of calpain and calpastatin
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 4:00 PM - 5:00 PM
Authors: *H. M. JOURDI1, N. IWATA2, T. C. SAIDO2, M. BAUDRY1;
1Neurosci Prog, Univ South California, Los Angeles, CA, 2Proteolytic Neurobiology, RIKEN-Brain Science Institute, Wako City, Saitama, JAPAN.
Prolonged exposure of cultured hippocampal slices to positive modulators of AMPArs (a.k.a. ampakines) causes a down-regulation of AMPArs, an effect mediated by calpain activation and the resulting degradation of SAP97 and GRIP1, two AMPAr-interacting PDZ proteins (Jourdi et al., 2005). In the present study, we used primary neuronal cultures to analyze the mechanisms involved in ampakine-mediated down-regulation of AMPArs. Brief treatment of dissociated neurons with the ampakine CX614 resulted in a biphasic effect on the levels of AMPArs; 4 hr after addition of CX614, levels of AMPA receptors subunits were increased, while after 8 hr, levels were decreased. This decrease was associated with calpain-mediated degradation of GRIP1 and SAP97, an effect similar to that previously observed in cultured hippocampal slices. As CX614-induced down-regulation of AMPAr protein levels might be preceded by internalization of surface-bound receptors, we analyzed the interaction of ampakines with signaling pathways known to be involved in AMPAr internalization, such as the NMDA receptor - protein kinase C pathway. To further assess the role of calpain in ampakine-mediated down-regulation of AMPA receptors and BDNF regulation, we performed similar experiments in cultured slices prepared from mice lacking or over-expressing the endogenous inhibitor of calpain, calpastatin. Our results indicate that prolonged activation of AMPA receptors results in calpain-mediated degradation of AMPA receptor-interacting proteins and internalization and down-regulation of AMPA receptors. These results provide important information regarding mechanisms of synaptic plasticity and of the roles of calpains in these processes. <<<
