Proteolysis of glutamate receptor-interacting protein by calpain in rat brain: implications for synaptic plasticity

Activation of the calcium-dependent protease calpain has been proposed to b e a key step in synaptic plasticity in the hippocampus. However, the exact pathway through which calpain mediates or modulates changes in synaptic fun ction remains to be clarified, Here we report that glutamate receptor-inter acting protein (GRIP) is a substrate of calpain, as calpain-mediated GRIP d egradation was demonstrated using three different approaches: (i) purified calpain I digestion of synaptic membranes, (ii) calcium treatment of frozen -thawed brain sections, and (iii) NMDA-stimulated organotypic hippocampal s lice cultures. More importantly, calpain activation resulted in the disrupt ion of GRIP binding to the GluR2 subunit of alpha -amino-3-hydroxy-5-methyl isoxazole-4propionate (AMPA) receptors. Because GRIP has been proposed to f unction as an AMPA receptor-targeting and synaptic-stabilizing protein, as well as a synaptic-organizing molecule, calpain-mediated degradation of GRI P and disruption of AMPA receptor anchoring are likely to play important ro les in the structural and functional reorganization accompanying synaptic m odifications in long-term potentiation and long-term depression.