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Hippocalcin functions as a calcium sensor in hippocampal LTD
Claire L Palmer1, Wonil Lim, Peter G R Hastie
1MRC Centre for Synaptic Plasticity, Department of Anatomy, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, United Kingdom.
Neuron
|August 17, 2005
Summary
Hippocalcin acts as a calcium sensor, binding to the AP2 complex to mediate calcium-dependent endocytosis of AMPA receptors (AMPARs) during NMDAR-dependent long-term depression (LTD). This mechanism is crucial for LTD but not long-term potentiation (LTP).
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- The precise mechanism linking NMDAR-dependent long-term depression (LTD) to Ca(2+)-dependent endocytosis of AMPA receptors (AMPARs) remains unclear.
- Understanding this process is vital for comprehending synaptic plasticity and memory formation.
Purpose of the Study:
- To elucidate the molecular players involved in coupling NMDAR activation to AMPAR endocytosis during LTD.
- To identify the Ca(2+) sensor responsible for initiating AMPAR internalization in response to NMDAR activation.
Main Methods:
- Co-immunoprecipitation assays to assess protein-protein interactions.
- Biochemical analysis of Ca(2+) sensitivity of protein complexes.
- Electrophysiological recordings in neurons to study synaptic plasticity (LTD and LTP).
- In vivo infusion of truncated hippocalcin mutants.
Main Results:
- Hippocalcin directly binds to the beta2-adaptin subunit of the AP2 adaptor complex.
- Hippocalcin and GluR2 co-immunoprecipitate in a Ca(2+)-sensitive manner.
- Infusion of a Ca(2+)-binding deficient hippocalcin mutant (HIP(2-72)) selectively blocked synaptically evoked LTD, without affecting LTP.
Conclusions:
- The AP2-hippocalcin complex functions as a critical Ca(2+) sensor.
- This complex couples NMDAR-dependent Ca(2+) signaling to the regulated endocytosis of AMPARs.
- The findings reveal a novel molecular mechanism underlying LTD at the synapse.