Physiological and Pathological Activation of Neuronal Calpains (Animations)

Jing Liu,1* Ming Cheng Liu, Kevin K. W. Wang

1Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry, McKnight Brain Institute, Post Office Box 100256, University of Florida, Gainesville, FL 32610, USA.

2Center for Traumatic Brain Injury Studies, Department of Neuroscience, McKnight Brain Institute, Post Office Box 100256, University of Florida, Gainesville, FL 32610, USA.

3Center of Innovative Research, Banyan Biomarkers, Incorporated, 12085 Research Drive, Alachua, FL 32615, USA.


These animations show the activation and actions of neuronal calpains under physiological and pathophysiological conditions.

Animation 1. In glutaminergic neurons, a nerve impulse (white wave) elicits a physiological increase in presynaptic calcium concentration (red). This stimulates controlled glutamate release and thereby a transient increase in synaptic glutamate (small green spheres), which is cleared by an ATP-dependent glutamate transporter (green oval in presynaptic membrane) and on glial cell membranes (not shown). NMDA receptor activation leads to a transient increase in postsynaptic calcium concentration (red), allowing calcium (small red sphere) to bind to and activate calpain.

In the "Calpain stimulated synaptic remodeling" sequence, the activated calcium-bound form of calpain (yellow) cleaves postsynaptic cytoskeletal and scaffolding proteins, thereby promoting reorganization of the postsynaptic density and synaptic remodeling. Under physiological conditions, the increase in intracellular calcium concentration is transient, and calpain returns to its inactive state as intracellular calcium concentration returns to normal, as a result of calcium removal by the Na+/Ca2+ exchanger-3 and calcium pumps (not shown).

In addition, as shown in the "Calpain stimulated gene expression" sequence, calpain-mediated cleavage of β-catenin and SCOP may stimulate gene transcription and thereby the production of proteins involved in synaptic remodeling. Again, calpain returns to its inactive state as intracellular calcium concentration returns to normal.

[Play Animation 1]

Animation 2. In glutamatergic neurons subjected to pathological conditions (indicated by orange color), calcium (red) floods into the nerve terminal. This results in excessive synaptic glutamate release, which is exacerbated by decreased ATP synthesis and the ensuing decline in glutamate uptake. Glutamate then binds to various glutamate receptors. Sodium influx (blue spheres) through the AMPA receptor depolarizes the postsynaptic cell, enabling NMDA receptor activation. Calcium enters through the NMDA receptor and may also enter through voltage-gated calcium channels (VGCC, yellow) once the plasma membrane is sufficiently depolarized. Glutamate activation of the mGluR1α metabotropic glutamate receptor stimulates activation of the neuroprotective PI3K-AKT pathway as well as stimulating the production of IP3 (small yellow sphere) by phospholipase C (PLC, blue circle). IP3 stimulates the release of additional calcium from ER stores. Calcium may also be released from the mitochondria. Calpain cleavage of the C-terminal cytoplasmic tail of mGluR1α abrogates its activation of PI3K-AKT signaling. The calcium overload resulting from all of these processes triggers pathological calpain activation (yellow), leading to extensive neuroprotein degradation, inactivation of the Na+/Ca2+ exchanger (NCX3, pale blue oval) and neuronal death. Protein breakdown products released into the extracellular compartment could be used as biomarkers for neuronal injury.

[Play Animation 2]

Technical Details

Format: Flash

Size: Animation 1: 460 KB

Size: Animation 2: 475 KB

Requirements: This animation will play with Macromedia Flash 5 ( or higher.

*Corresponding authors. E-mail: jingl{at}; kwang{at}

Citation: J. Liu, M. C. Liu, K. K. W. Wang, Calpain in the CNS: From synaptic function to neurotoxicity. Sci. Signal. 1, re1 (2008).

© 2008 American Association for the Advancement of Science