Hippocalcin Functions as a Calcium Sensor in Hippocampal LTD

It is not fully understood how NMDAR-dependent LTD causes Ca2+-dependent endocytosis of AMPARs. Here we show that the neuronal Ca2+ sensor hippocalcin binds the β2-adaptin subunit of the AP2 adaptor complex and that along with GluR2 these coimmunoprecipitate in a Ca2+-sensitive manner. Infusion of a truncated mutant of hippocalcin (HIP2-72) that lacks the Ca2+ binding domains prevents synaptically evoked LTD but has no effect on LTP. These data indicate that the AP2-hippocalcin complex acts as a Ca2+ sensor that couples NMDAR-dependent activation to regulated endocytosis of AMPARs during LTD.