Direct cleavage of AMPA receptor subunit GluR1 and suppression of AMPA currents by caspase-3: implications for synaptic plasticity and excitotoxic neuronal death.
ABSTRACT 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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ABSTRACT: Emerging evidence suggests that apoptosis regulators and executioners may control cell fate, without involving cell death per se. Indeed, several conserved elements of apoptosis are integral components of terminal differentiation, which must be restrictively activated to assure differentiation efficiency, and carefully regulated to avoid cell loss. A better understanding of the molecular mechanisms underlying key checkpoints responsible for neural differentiation, as an alternative to cell death will surely make stem cells more suitable for neuro-replacement therapies. In this review, we summarize recent studies on the mechanisms underlying the non-apoptotic function of p53, caspases, and Bcl-2 family members during neural differentiation. In addition, we discuss how apoptosis-regulatory proteins control the decision between differentiation, self-renewal, and cell death in neural stem cells, and how activity is restrained to prevent cell loss.Molecular Neurobiology 07/2012; 46(2):316-31. · 5.47 Impact Factor
Dataset: artigo Carlos e meu Neuroscience
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ABSTRACT: Recent studies of the molecular mechanisms of long-term depression (LTD) suggest a crucial role for the signalling pathways of apoptosis (programmed cell death) in the weakening and elimination of synapses and dendritic spines. With this backdrop, we suggest that LTD can be considered as the electrophysiological aspect of a larger cell biological programme of synapse involution, which uses localized apoptotic mechanisms to sculpt synapses and circuits without causing cell death.Philosophical Transactions of The Royal Society B Biological Sciences 01/2014; 369(1633):20130138. · 6.23 Impact Factor