[Frontiers in Bioscience S1, 466-476, June 1, 2009]

Calpain and the Glutamatergic Synapse

Shachee Doshi1, David R. Lynch1, 2

1Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 2Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania

TABLE OF CONTENTS

1. ABSTRACT
2. Introduction
3. Calpain - a major neuronal protease
4. Glutamate receptors and calpain
4.1. The NMDA receptor and calpain
4.1.1. The NMDA receptor as a calpain substrate
4.1.2. Control of calpain-mediated cleavage of NMDARs: MAGUKS and tyrosine kinases
4.2. The AMPA receptor and calpain
4.2.1. Control of calpain-mediated cleavage of AMPARs by kinases
4.3. The metabotropic glutamate receptor and calpain
5. Conclusion
6. Acknowledgements
7. References

1. ABSTRACT

Calpain is a ubiquitous protease found in different tissue types and in many organisms including mammals. It generally does not destroy its large variety of substrates, but more commonly disrupts their function. In neurons, many of its substrates become dysregulated as a result of cleavage of their regulatory domain by this protease, leading to altered signaling between cells. In glutamatergic synaptic transmission, direct targets of calpain include all of the major glutamate receptors: NMDA receptors, AMPA receptors and mGluR. By cleaving these receptors and associated intracellular proteins, calpain may regulate the physiology at glutamatergic synapses. As a result, calpain-mediated cleavage in neurons might not only be involved in pathological events like excitotoxicity, but may also have neuroprotective effects and roles in physiological synaptic transmission.