Sci. Signal., 10 June 2008 Vol. 1, Issue 23, p. tr3 [DOI: 10.1126/scisignal.123tr3]
Physiological and Pathological Actions of Calpains in Glutamatergic Neurons Jing Liu1*, Ming Cheng Liu2,3, and Kevin K. W. Wang1,2,3* 1
Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry, McKnight Brain Institute, Post Office Box 100256, University of Florida, Gainesville, FL 32610, USA. 2 Center for Traumatic Brain Injury Studies, Department of Neuroscience, McKnight Brain Institute, Post Office Box 100256, University of Florida, Gainesville, FL 32610, USA. 3 Center of Innovative Research, Banyan Biomarkers, Incorporated, 12085 Research Drive, Alachua, FL 32615, USA. Abstract: These animations show the activation and actions of neuronal calpains under physiological and pathophysiological conditions. They emphasize how physiological events involved in excitatory neurotransmission and synaptic plasticity—such as glutamate release, calcium influx, and activation of postsynaptic calpains—can become destructive under pathological conditions. These animations would be useful in a neurobiology or neuroscience course, where they could be used to illustrate proteolytic mechanisms underling activitydependent synaptic plasticity, and how excessive activation of these signaling mechanisms can lead to excitotoxic neuronal death. Description Animation 1. In glutamatergic 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, calpainmediated 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.
Abbreviations used in Animation 1 include AMPAR, -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid–type glutamate receptor; ATP, adenosine triphosphate; Ca2+, calcium; CREB, cyclic adenosine monophosphate (cAMP) response element (CRE) binding protein; GRIP, glutamate receptor–interacting protein; MAPK, mitogen-activated protein kinase; NMDAR, N-methyl-D-aspartate–type glutamate receptor; PSD-95, postsynaptic density-95 scaffolding protein; SCOP, suprachiasmatic nucleus circadian oscillatory protein Tcf/Lef, T cell factor/lymphoid enhancer factor family transcription factor; VGCC, voltagegated calcium channel [Play Animation 1 (http://stke.sciencemag.org/feature/Liu/Animation1.html)]
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 mGluR1 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 mGluR1 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. Abbreviations used in Animation 2 include AMPAR, -amino-3-hydroxy-5-methyl-4isoxazolepropionic acid–type glutamate receptor; ATP, adenosine triphosphate; Ca2+,
calcium; ER, endoplasmic reticulum; IP3, inositol 1,4,5-trisphosphate, IP3R, IP3 receptor; mGluR1 , metabotropic glutamate receptor type 1 , NMDAR, N-methyl-D-aspartate–type glutamate receptor; PI3K-AKT, phosphoinositide 3-kinase-Akt signaling pathway; PLC, phospholipase C; NCX3, Na+/Ca2+ exchanger 3; VGCC, voltage-gated calcium channel
[Play Animation 2 (http://stke.sciencemag.org/feature/Liu/Animation2.html)] Educational Details Learning Resource Type: Animation Context: Undergraduate upper division, graduate, professional (degree program) Intended Users: Teacher, learner Intended Educational Use: Teach, learn Discipline: Neurobiology, Cell Biology Keywords: signal transduction, calpain, calcium, glutamate, action potential, synaptic plasticity, neurotoxicity, biomarkers, movie Technical Details Format: Macromedia Flash
Size: 460 KB (Animation 1), 475 KB (Animation 2) Requirements: Macromedia Flash 5 (http://www.macromedia.com/downloads/) or higher. Related Resources Review J. Liu, M. C. Liu, K. K. W. Wang, Calpain in the CNS: From synaptic function to neurotoxicity. Sci. Signal. 1, re1 (2008). [Gloss] [Abstract] [Full Text] Limits for Use Cost: Free Rights: This material may be downloaded, printed, linked to, and/or redistributed without modification for non-commercial, course teaching purposes only, provided credit to Science Signaling is included by listing the citation for the teaching resource.
*Corresponding authors. E-mail:
[email protected];
[email protected] Citation: J. Liu, M. C. Liu, K. K. W. Wang, Physiological and Pathological Actions of Calpains in Glutamatergic Neurons. Sci. Signal. 1, tr3 (2008).
