Selective activation induced cleavage of the XXXX subunit by calpain.

@entity4319 @entity63 @entity16 @entity4476 @entity143 @entity460 @entity35 @entity3390
Although activation of @entity460 -activated neutral protease (calpain) by the @entity143 receptor has been suggested to play critical roles in synaptic modulation and @entity16 , the nature of its substrates has not been completely defined. In this study, we examined the ability of calpain to cleave the @entity143 receptor in cultured hippocampal neurons. Activation of the @entity143 receptor by agonist application led to rapid calpain-specific proteolysis of spectrin and decreased levels of @entity4476 /2B subunits. Cleavage of the @entity4476 /2B subunit created a 115 kDa product that retained the ability to bind 125I- @entity3390 and is predicted to be active. Increases in levels of this product appeared within 5 min of @entity143 receptor activation and were stable for periods of >30 min. Subtype-specific antibodies demonstrated that the @entity4319 subunit was cleaved in these primary cultures, but the @entity4476 subunit was not. An inhibitor of calpain blocked both the decrease of intact @entity4319 and the increase of the low molecular weight form, whereas neither caspase nor cathepsin inhibitors had an effect on these events. Cell surface biotinylation experiments demonstrated that the 115 kDa fragment remained on the cell surface. This @entity4319 fragment was also found in the @entity35 hippocampus after transient @entity63 , showing that this process also occurs in vivo. This suggests that calpain-mediated cleavage of the @entity4319 subunit occurs in neurons and gives rise to active @entity143 receptor forms present on the cell surface after excitotoxic glutamatergic stimulation. Such forms could contribute to excitotoxicity and synaptic remodeling.
