Calpain I activation in rat hippocampal neurons in culture is NMDA receptor selective and not essential for excitotoxic cell death

Adamec, Emil; Beermann, Mary Lou; Nixon, Ralph A.

doi:10.1016/s0169-328x(97)00304-5

Cited by 66 publications

(50 citation statements)

References 70 publications

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“…Alternatively, CRHR1 internalization (Holmes et al (2006); Reyes et al, 2006Reyes et al, , 2008 might influence the anchoring or trafficking of closely located NMDA receptors within the postsynaptic density. Here we found that CRH enhanced the NMDA-dependent (Adamec et al, 1998) activity of calpain, which was required for spine loss. However, it is feasible that other mechanisms exist, including, for example, augmentation or inhibition of NMDA receptor-mediated changes of actinregulating Rho GTPases (Swinny and Valentino, 2006;Chen et al, 2013).…”

Section: How Might Crh Receptor Occupancy Interact With Glutamate Recmentioning

confidence: 59%

“…Spectrin cleavage disrupts the spine cytoskeleton as well as the organization of the postsynaptic density (Dosemeci and Reese, 1995). Previous work has shown that calpain activation in hippocampal neurons depends on NMDA receptor activation (Adamec et al, 1998) and that antagonists to NMDA receptors prevent the activation of calpain (del Cerro et al, 1994).…”

Section: Crh-induced Spine Loss Requires Activation Of Nmda Receptorsmentioning

confidence: 99%

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NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH

et al. 2013

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The complex effects of stress on learning and memory are mediated, in part, by stress-induced changes in the composition and structure of excitatory synapses. In the hippocampus, the effects of stress involve several factors including glucocorticoids and the stress-released neuropeptide corticotropin-releasing hormone (CRH), which influence the integrity of dendritic spines and the structure and function of the excitatory synapses they carry. CRH, at nanomolar, presumed-stress levels, rapidly abolishes short-term synaptic plasticity and destroys dendritic spines, yet the mechanisms for these effects are not fully understood. Here we tested the hypothesis that glutamate receptor-mediated processes, which shape synaptic structure and function, are engaged by CRH and contribute to spine destabilization. In cultured rat hippocampal neurons, CRH application reduced dendritic spine density in a time-and dose-dependent manner, and this action depended on the CRH receptor type 1. CRH-mediated spine loss required network activity and the activation of NMDA, but not of AMPA receptors; indeed GluR1-containing dendritic spines were resistant to CRH. Downstream of NMDA receptors, the calciumdependent enzyme, calpain, was recruited, resulting in the breakdown of spine actin-interacting proteins including spectrin. Pharmacological approaches demonstrated that calpain recruitment contributed critically to CRH-induced spine loss. In conclusion, the stress hormone CRH co-opts mechanisms that contribute to the plasticity and integrity of excitatory synapses, leading to selective loss of dendritic spines. This spine loss might function as an adaptive mechanism preventing the consequences of adverse memories associated with severe stress.

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Section: How Might Crh Receptor Occupancy Interact With Glutamate Recmentioning

confidence: 59%

Section: Crh-induced Spine Loss Requires Activation Of Nmda Receptorsmentioning

confidence: 99%

NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH

et al. 2013

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“…This observation is in agreement with previous studies by other groups, showing that the VSCC pathway of Ca 2 þ entry is not particularly toxic to cells 34 or involved in calpain activation. 35 Ca 2 þ entering the cell by specific entry points is more efficient in triggering cell death than other pathways -source-specificity hypothesis. 36 Up to now, Ca 2 þ -permeable glutamate receptors were considered to be associated with source-specific toxicity, particularly NMDA receptors.…”

Section: Discussionmentioning

confidence: 99%

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

et al. 2007

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Proteolytic cleavage of the Na þ /Ca 2 þ exchanger (NCX) by calpains impairs calcium homeostasis, leading to a delayed calcium overload and excitotoxic cell death. However, it is not known whether reversal of the exchanger contributes to activate calpains and trigger neuronal death. We investigated the role of the reversal of the NCX in Ca 2 þ dynamics, calpain activation and cell viability, in a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-stimulated hippocampal neurons. The sodium-calcium exchanger (NCX) plays a fundamental role in controlling Na þ and Ca 2 þ homeostasis. 1,2 NCX primarily extrudes Ca 2 þ in exchange for Na þ , whereas upon neuronal depolarization, Na þ is pumped out by NCX, while Ca 2 þ is pumped in. In pathophysiological conditions, overactivation of glutamate receptors can cause the reversal of NCX, leading to Ca 2 þ entry into the cell. 3 Three NCX genes have been identified, NCX1, 4 NCX2 5 and NCX3. 6 In excitotoxic cell death, an increase in intracellular free calcium concentration ([Ca 2 þ ] i ) may directly cause activation of Ca 2 þ -dependent cysteine proteases, the calpains. Calpains modulate a variety of physiological processes, 7 and are important mediators of cell death. 8,9 Calpains mediate the neurotoxic effect of N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons by a caspase-independent cell death mechanism of excitotoxicity. 10 Calpains are also involved in the neurotoxic effect caused by a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor activation in cultured hippocampal neurons, 11 and in hippocampal slice cultures. 12 During excitotoxic neurodegeneration, calpains are responsible for the proteolysis of several cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters. 13 Recently, the involvement of calpains in the cleavage of NCX was described in cultured cerebellar granule neurons exposed to glutamate and following brain ischemia. 14 The NCX3 subtype is inactivated by proteolytic cleavage by calpains, and is no longer able to pump Ca 2 þ out of the cell, thus enhancing cell death. Furthermore, NCX3 was shown to be more relevant for cell survival than NCX1 or NCX2, namely in cultured cerebellar granule neurons. 14, 15 We recently reported that neurotoxicity induced by activation of AMPA receptors is characterized by calpain activation, lack of caspase activation, nuclear condensation/fragmentation, release of cytochrome c from mitochondria, decreased intracellular ATP levels, production of nitric oxide, moderate superoxide production and increased levels of peroxynitrite. [16][17][18] In this in vitro model of excitotoxicity, the cell

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“…Alternatively, CBD3 could inhibit calpain-dependent cleavage of CRMP2 by inhibiting Ca 2ϩ influx required for calpain activation. Thus, we asked if TAT-CBD3 could alter calpain cleavage of CRMP2 following glutamate-or ionomycin-induced activation of calpain (44). Lysates from 7 DIV neurons were subjected to a 30-min Glu/Ser stimulation and immunoblotted with a CRMP2 antibody that recognizes C-terminal cleaved and full-length CRMP2.…”

Section: Tat-cbd3 Reduces Calpain Cleavage Of Crmp2-crmp2mentioning

confidence: 99%

Neuroprotection against Traumatic Brain Injury by a Peptide Derived from the Collapsin Response Mediator Protein 2 (CRMP2)

Brittain

Chen

Wilson

et al. 2011

Journal of Biological Chemistry

111

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Background: CRMP2 is an axonal guidance protein that has been linked to NMDA receptor-mediated excitotoxicity. Results: A CRMP2 peptide protects against NMDA receptor-mediated excitotoxicity in vitro and in vivo following a traumatic brain injury. Conclusion: CRMP2 is a novel target for neuroprotection. Significance: Targeting CRMP2 could lead to development of neurotherapeutics against traumatic brain injury as well as other neuronal insults.

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Calpain I activation in rat hippocampal neurons in culture is NMDA receptor selective and not essential for excitotoxic cell death

Cited by 66 publications

References 70 publications

NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH

NMDA Receptor Activation and Calpain Contribute to Disruption of Dendritic Spines by the Stress Neuropeptide CRH

Changes in calcium dynamics following the reversal of the sodium-calcium exchanger have a key role in AMPA receptor-mediated neurodegeneration via calpain activation in hippocampal neurons

Neuroprotection against Traumatic Brain Injury by a Peptide Derived from the Collapsin Response Mediator Protein 2 (CRMP2)

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