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Calpain‐mediated degradation of G‐substrate plays a critical role in retinal excitotoxicity for amacrine cells
Author(s) -
Nakazawa Toru,
Shimura Masahiko,
Mourin Ryu,
Kondo Mineo,
Yokokura Shunji,
Saido Takaomi C.,
Nishida Kohji,
Endo Shogo
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21953
Subject(s) - excitotoxicity , calpain , nmda receptor , microbiology and biotechnology , neuroprotection , biology , retina , chemistry , biochemistry , neuroscience , receptor , enzyme
The role of neuronal N‐methyl‐D‐aspartate (NMDA) receptor‐mediated intracellular signaling has been elucidated in both physiological and pathological conditions. However, the details of relative vulnerability for excitotoxicity remain unknown. Retinal excitotoxicity is involved in various diseases leading to irreversible blindness. Here, we used the visual system and explored the mechanistic details of the NMDA‐elicited intracellular events, especially in the amacrine cells, which are the most vulnerable type of neuron in the retina. G‐substrate, a specific substrate of cyclic guanosine 3′,5′‐monophosphate (cGMP)‐dependent protein kinase, is colocalized with amacrine cells and acts as an endogenous inhibitor of protein phosphatase. To elucidate how G‐substrate was involved in NMDA‐induced amacrine cell death, the immunohistochemical analysis with G‐substrate antibody was performed following NMDA injury. In vivo, NMDA immediately decreased G‐substrate immunoreactivity, and the suppression of calpain activation using ALLN or calpain III, an inhibitor of calpain, blocked this decrease. In vitro, degraded fragments of G‐substrate were detected within 10 min after coincubation of G‐substrate and calpain. Moreover, G‐substrate knockout (G‐substrate −/− ) mice were more susceptible to NMDA injury than wild‐type mice. ALLN did not have a neuroprotective effect in G‐substrate −/− mice. These data strongly suggest that calpain‐mediated loss of G‐substrate represents an important mechanism contributing to NMDA‐induced amacrine cell death. © 2008 Wiley‐Liss, Inc.