CALPAIN-MEDIATED REGULATION OF NMDA RECEPTOR STRUCTURE AND FUNCTION

Calpains have been previously shown to regulate AMPA receptor properti es by producing partial truncation of the C-terminal domains of severa l receptor subunits. We now report that NMDA receptor subunits, in par ticular NR2 subunits, are also subjected to calpain-mediated truncatio n. Treatment of synaptic membranes with calpain I resulted in truncati on of both NR1 and NR2 subunits, with the appearance of NR2 species wi th lower mol.wt. than native subunits, but still recognized by antibod ies directed at the C-terminal domain. This treatment did not modify t he binding of several Ligands of the NMDA receptors, such as glutamate , glycine or TCP. Incubation of thin frozen-thawed brain sections with calcium resulted in calpain-mediated selective degradation of NR2 sub units, as truncation into smaller fragments was totally blocked by cal pain inhibitors. Under the same conditions, TCP binding to sections wa s decreased by about 50%, an effect also blocked by calpain inhibitors . Treatment of hippocampal slices in culture with the excitotoxin, kai nic acid, also produced calpain-mediated truncation of the C-terminal domain of NR2 but not NR1 subunits of the NMDA receptors. The results indicate that calpain activation produces several modifications of NMD A receptors, including the truncation of the C-terminal domain of NR2 subunits, and changes in channel binding properties. They suggest that calpain-mediated regulation of NMDA receptors might represent a feed- back regulation of the receptors which could be used to limit receptor activation. (C) 1998 Elsevier Science B.V.