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Regulation of CaMKII activity by oxidative modifications through glutathionylation and aggregation
Author(s) -
SHETTY PAVAN KUMAR,
HUANG FREESIA L,
HUANG KUOPING
Publication year - 2006
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.20.5.lb60-c
Subject(s) - autophosphorylation , chemistry , biochemistry , glutathione , kinase , protein kinase a , neurotransmission , cgmp dependent protein kinase , microbiology and biotechnology , enzyme , biology , mitogen activated protein kinase kinase , receptor
CaMKII is one of the most abundant kinases in neurons and it has been implicated in the regulation of diverse neural functions. This kinase contains several reactive sulfhydryl groups, which are potential targets of oxidants generated during normal neurotransmission as well as under pathological condition. Previously, we showed that treatment of rat brain slices with oxidants generated two reactive thionylating agents, glutathione disulfide S‐monoxide (GS‐DSMO) and S‐dioxide (GS‐DSDO). In vitro, treatment of mouse brain CaMKII with these oxidants caused glutathionylation and aggregation of the kinase. Interestingly, GS‐DSMO mainly modified the α isoform of CaMKII, whereas, both α and β CaMKII were modified by GS‐DSDO. Modification of CaMKII by GS‐DSMO only caused a minor inactivation of the enzyme; in contrast, that by GS‐DSDO resulted in a dose‐dependent inhibition of autophosphorylation of the kinase as well as its activity toward exogenous substrate. Treatment of mouse brain synaptosomes with oxidants, such as H2O2, diamide, and sodium nitroprusside, caused thionylation and aggregation of proteins that were detectable by immunoblot with antibodies against GSH‐associated protein. These treatments of synaptosomes primarily caused CaMKII to form aggregates with a concomitant reduction of the kinase activity. These findings suggest that oxidants generated during normal synaptic stimulation or under pathological conditions could modulate CaMKII activity through thionylation as well as the formation of aggregates.