Calpain-mediated degradation of G-substrate plays a critical role in retinal excitotoxicity for amacrine cells

Toru Nakazawa, Masahiko Shimura, Ryu Mourin, Mineo Kondo, Shunji Yokokura, Takaomi C. Saido, Kohji Nishida, Shogo Endo

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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 wildtype 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.

Original languageEnglish
Pages (from-to)1412-1423
Number of pages12
JournalJournal of Neuroscience Research
Volume87
Issue number6
DOIs
Publication statusPublished - 2009 May 1

Keywords

  • Calpain
  • Excitatory amino acids
  • G-substrate
  • Neuroprotection
  • Signal transduction

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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