Abstract
We have recently demonstrated that in resting conditions calpain 1, but not calpain 2, is specifically associated to the N-Methyl-D-Aspartate receptor (NMDAR) multiprotein complex. We are here reporting that in SKNBE neuroblastoma cells or in freshly isolated nerve terminals from adult rat hippocampus, the proteolytic activity of calpain 1 resident at the NMDAR is very low under basal conditions and greatly increases following NMDAR stimulation. Since the protease resides at the NMDAR in saturating amounts, variations in Ca2+ influx promote an increase in calpain 1 activity without affecting the amount of the protease originally associated to NMDAR. In all the conditions examined, resident calpain 1 specifically cleaves NR2B at the C-terminal region, leading to its internalization together with NR1 subunit. While in basal conditions intracellular membranes include small amounts of NMDAR containing the calpain-digested NR2B, upon NMDAR stimulation nearly all the receptor molecules are internalized. We here propose that resident calpain 1 is involved in NMDAR turnover, and following an increase in Ca2+ influx, the activated protease, by promoting the removal of NMDAR from the plasma membranes, can decrease Ca2+ entrance through this channel. Due to the absence of calpastatin in such cluster, the activity of resident calpain 1 may be under the control of HSP90, whose levels are directly related to the activation of this protease. Observations of different HSP90/calpain 1 ratios in different ultrasynaptic compartments support this conclusion.
Highlights
Multiple lines of evidence indicate that the Ca2+-dependent protease calpain plays critical roles in both physiological and pathological conditions [1,2,3,4,5,6]
In SKNBE neuroblastoma cells, the chaperone HSP90 plays a specific role in the control of the dynamic activation of calpain 1 and that the chaperone can assist the protease during its recruitment in the multiprotein N-Methyl-D-Aspartate receptor (NMDAR) cluster [34]
It is well known that Ca2+ entry through NMDAR, mediates various neuronal activities and signaling pathways, and induces calpain activation that in turn catalyzes the selective processing of the receptor [4, 8, 11, 16, 51, 52]
Summary
Multiple lines of evidence indicate that the Ca2+-dependent protease calpain plays critical roles in both physiological and pathological conditions [1,2,3,4,5,6]. In SKNBE neuroblastoma cells, the chaperone HSP90 plays a specific role in the control of the dynamic activation of calpain 1 and that the chaperone can assist the protease during its recruitment in the multiprotein NMDAR cluster [34]. These observations are consistent with the finding that calpain 1, but not calpain 2, resides in small but saturating amounts at the NMDAR complex together with a large excess of HSP90 [34]
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