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Cleavage of the Ves...
Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites.
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Rodrigues Gomes, Joao Carlos (author)
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Lobo, Andrea C (author)
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Melo, Carlos V (author)
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- Inacio, Ana (author)
- Lund University,Lunds universitet,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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Takano, Jiro (author)
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Iwata, Nobuhisa (author)
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Saido, Takaomi C (author)
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de Almeida, Luís P (author)
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- Wieloch, Tadeusz (author)
- Lund University,Lunds universitet,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine
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Duarte, Carlos B (author)
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(creator_code:org_t)
- 2011
- 2011
- English.
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In: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 31:12, s. 4622-4635
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Abstract
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- GABA is the major inhibitory neurotransmitter in the CNS and changes in GABAergic neurotransmission affect the overall activity of neuronal networks. The uptake of GABA into synaptic vesicles is mediated by the vesicular GABA transporter (VGAT), and changes in the expression of the transporter directly regulate neurotransmitter release. In this work we investigated the changes in VGAT protein levels during ischemia and in excitotoxic conditions, which may affect the demise process. We found that VGAT is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, giving rise to a stable truncated cleavage product (tVGAT). VGAT cleavage was also observed after transient middle cerebral artery occlusion in mice, a cerebral ischemia model, and following intrahippocampal injection of kainate, but no effect was observed in transgenic mice overexpressing calpastatin, a calpain inhibitor. Incubation of isolated cerebrocortical synaptic vesicles with recombinant calpain also induced the cleavage of VGAT and formation of stable tVGAT. Immunoblot experiments using antibodies targeting different regions of VGAT and N-terminal sequencing analysis showed that calpain cleaves the transporter in the N-terminal region, at amino acids 52 and 60. Immunocytochemistry of GABAergic striatal neurons expressing GFP fusion proteins with the full-length VGAT or tVGAT showed that cleavage of the transporter induces a loss of synaptic delivery, leading to a homogeneous distribution of the protein along neurites. Our results show that excitotoxicity downregulates full-length VGAT, with a concomitant generation of tVGAT, which is likely to affect GABAergic neurotransmission and may influence cell death during ischemia.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Rodrigues Gomes, ...
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Lobo, Andrea C
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Melo, Carlos V
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Inacio, Ana
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Takano, Jiro
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Iwata, Nobuhisa
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show more...
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Saido, Takaomi C
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de Almeida, Luís ...
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Wieloch, Tadeusz
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Duarte, Carlos B
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
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The Journal of N ...
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Lund University