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Involvement of calpain in AMPA‐induced toxicity to rat cerebellar Purkinje neurons
Author(s) -
Mansouri Bobbak,
Henne William Michael,
Attridge Jennifer,
Bliss Richard Michael,
Bahr Ben A,
Strahlendorf Howard K,
Strahlendorf Jean C
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1342
Subject(s) - ampa receptor , calpain , microbiology and biotechnology , purkinje cell , excitotoxicity , cnqx , spectrin , chemistry , neuroscience , cerebellum , glutamate receptor , biology , receptor , cytoskeleton , cell , biochemistry , enzyme
AMPA excitotoxicity is manifested as a type of programmed cell death (PCD) termed dark cell, which is linked to increased intracellular Ca2+. Cytoskeletal changes in response to AMPA receptor activation, coupled with increased intracellular Ca2+ concentration suggests activation of destructive enzymes such as calpains, Ca2+‐dependent cysteine proteases. Since calpains and AMPA have been linked to both necrotic cell death and PCD, we sought to determine the role of calpains in mediating both types toxicity in Purkinje neurons of the cerebellum. These studies employed immunohistochemistry coupled with confocal microscopy and pharmacological interventions with calpain and AMPA receptor antagonists. The present study identifies an early involvement of calpains in mediating AMPA‐induced dark cell, but not edematous necrosis, based upon the effectiveness of AMPA to generate calpain‐derived a‐spectrin cleavage products in cerebellar Purkinje neurons that express dark cell, and the effectiveness of calpain antagonists, PD150606 and MDL28170 , to attenuate dark cell. The AMPA receptor antagonist CNQX, a proven inhibitor of AMPA‐elicited dark cell, also blocked AMPA‐induced increases in a‐spectrin, further suggesting interplay between AMPA receptor activation, calpain activation and dark cell. Since AMPA‐induced dark cell possesses morphological changes that resemble those that occur following many neurodegenerative events, the involvement of calpains is potentially far reaching and has widespread therapeutic implications in numerous CNS disorders.