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Neuronal Nitric Oxide Synthase and Calmodulin‐Dependent Protein Kinase IIα Undergo Neurotoxin‐Induced Proteolysis
Author(s) -
Hajimohammadreza Iradj,
Raser Kadee J.,
Nath Rathna,
Nadimpalli Ravi,
Scott Michele,
Wang Kevin K. W.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69031006.x
Subject(s) - calpain , excitotoxicity , biochemistry , biology , calmodulin , kainate receptor , neurotoxin , microbiology and biotechnology , nitric oxide synthase , chemistry , nmda receptor , ampa receptor , enzyme , receptor
Calpain (calcium‐activated neutral protease) has been implicated as playing a role of neuronal injury in cerebral ischemia and excitotoxicity. Here we report that, in addition to extreme excitotoxic conditions [ N ‐methyl‐ d ‐aspartate (NMDA), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA), and kainate challenges], other neurotoxins such as maitotoxin, A23187, and okadaic acid also induce calpain activation, as detected by m‐calpain autolytic fragmentation and nonerythroid α‐spectrin breakdown. Under the same conditions, calmodulin‐dependent protein kinase II‐α (CaMPK‐IIα) and neuronal nitric oxide synthase (nNOS) are both proteolytically cleaved by calpain. Such fragmentation can be reduced by calpain inhibitors (acetyl‐Leu‐Leu‐Nle‐CHO and PD151746). In vitro digestion of protein extract from cortical cultures with purified μ‐ and m‐calpain produced fragmentation patterns for CaMPK‐IIα and nNOS similar to those produced in situ. Also, several other calpain‐sensitive calmodulin‐binding proteins (plasma membrane calcium pump, microtubule‐associated protein 2, and calcineurin A) and protein kinase C‐α are also degraded in neurotoxin‐treated cultures. Lastly, in a rat pup model of acute excitotoxicity, intrastriatal injection of NMDA resulted in breakdown of CaMPK‐IIα and nNOS. The degradation of CaMPK‐IIα, nNOS, and other endogenous calpain substrates may contribute to the neuronal injury associated with various neurotoxins.