Direct cleavage of AMPA receptor subunit GluR1 and suppression of AMPA currents by caspase-3: implications for synaptic plasticity and excitotoxic neuronal death. NeuroMolecular Med. 1, 69-79

Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA.
NeuroMolecular Medicine (Impact Factor: 3.68). 02/2002; 1(1):69-79. DOI: 10.1385/NMM:1:1:69
Source: PubMed


Cysteine proteases of the caspase family play central roles in excecuting the cell death process in neurons during development of the nervous system and in neurodegenerative disorders. Recent findings suggest that caspases may also play roles in modulating neuronal plasticity in the absence of cell death. We previously reported that caspases can be activated in dendrites and synapses in response to activation of glutamate receptors. In the present study we demonstrate that the GluR1 subunit of the AMPA subtype of glutamate receptor is directly cleaved by caspase-3, and provide evidence that the cleavage of this subunit modulates neuronal excitability in ways that suggest important roles for caspases in regulating synaptic plasticity and cell survival. Whole-cell patch-clamp recordings in cultured rat hippocampal neurons showed that caspase activation in response to apoptotic stimuli selectively decreases AMPA channel activity without decreasing NMDA channel activity. Perfusion of neurons with recombinant caspase-3 resulted in a decreased AMPA current, demonstrating that caspase-3 activity is sufficient to suppress neuronal responses to glutamate. Exposure of radiolabeled GluR1 to recombinant caspase-3 resulted in cleavage of GluR1, demonstrating that this glutamate receptor protein is a direct substrate of this caspase. Our findings suggest roles for caspases in the modulation of neuronal excitability in physiological settings, and also identify a mechanism whereby caspases ensure that neurons die by apoptosis rather than excitotoxic necrosis in developmental and pathological settings.

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    • "The study of Gilman and Mattson [103] on neurons in apoptotic state have shown that activation of caspase-3 is followed by degradation of AMPA receptor, a part of R1 and R4 subunits of glutamate receptors, but not the NMDA receptors. Furthermore, it was shown that cultured hippocampal neurons treated with caspase-3 inhibitor exhibited increased function of AMPA receptors, what suggests that a low level of caspase activity is essential for reducing glutamate sensitivity in physiological conditions [104]. A study of Li et al. [105] merging overexpression of endogenous inhibitors and pharmacological inhibition of caspase-3 has shown that mitochondria mediated activation of caspase-3 is required for LTD in cell culture of CA1 hippocampal neurons. "
    Advances in Alzheimer's Disease 01/2015; 04(03):63-77. DOI:10.4236/aad.2015.43007
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    • "fficking by cleaving the AMPAR subunits GluR1 ( GluA1 ) ( Lu et al . 2002 ) and GluR4 ( GluA4 ) ( Chan et al . 1999 ; Glazner et al . 2000 ) , the AMPAR - associated proteins post - synaptic density - 95 ( PSD - 95 ) ( Liu et al . 2010 ) , CaMKII , calcineurin A , and the activity - regulated cytoskeleton - associated protein ( Arc ) ( Fig . 2 ) ( Lu et al . 2002 ; D ' Amelio et al . 2011 ; Jo et al . 2011 ; Snigdha et al . 2012 ) . LTD induction also requires caspase - 3 - mediated proteolysis of RAC - alpha serine / threonine - protein kinase ( Akt1 ) ( Li et al . 2010 ) . Active Akt1 suppresses LTD by phosphorylating and inhibiting the glycogen synthase kinase - 3β ( GSK3β ) , which also"
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