The ankyrin repeat-rich membrane spanning (ARMS)/Kidins220 scaffold protein is regulated by activity-dependent calpain proteolysis and modulates synaptic plasticity.

The expression of forms of synaptic plasticity, such as the phenomenon of long-term potentiation, requires the activity-dependent regulation of synaptic proteins and synapse composition. Here we show that ARMS (ankyrin repeat-rich membrane spanning protein)/Kidins220, a transmembrane scaffold molecule and BDNF TrkB substrate, is significantly reduced in hippocampal neurons after potassium chloride depolarization. The activity-dependent proteolysis of ARMS/Kidins220 was found to occur through calpain, a calcium-activated protease. Moreover, hippocampal long-term potentiation in ARMS/Kidins220(+/-) mice was enhanced, and inhibition of calpain in these mice reversed these effects. These results provide an explanation for a role for the ARMS/Kidins220 protein in synaptic plasticity events and suggest that the levels of ARMS/Kidins220 can be regulated by neuronal activity and calpain action to influence synaptic function.