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Pertussis toxin B-oligomer suppresses human immunodeficiency virus-1 Tat-induced neuronal apoptosis through feedback inhibition of phospholipase C-β by protein kinase C
Abstract Human immunodeficiency virus (HIV)-1 Tat is a multifunctional protein involved in viral replication, inflammation and apoptosis. Tat activates phospholipase C-β (PLC-β), presumably via a pertussis toxin (PTX) sensitive Gi protein, which is critical for neuronal apoptosis. In this study, we...
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Published in: | Neuroscience 2008-01, Vol.151 (2), p.525-532 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Abstract Human immunodeficiency virus (HIV)-1 Tat is a multifunctional protein involved in viral replication, inflammation and apoptosis. Tat activates phospholipase C-β (PLC-β), presumably via a pertussis toxin (PTX) sensitive Gi protein, which is critical for neuronal apoptosis. In this study, we show that Tat-mediated intracellular Ca2+ release in rat pheochromocytoma (PC-12) cells and rat primary cortical neuronal cultures was abrogated by pretreatment with either pertussis toxin and/or its B-oligomer subunit (PTX-B), devoid of ADP ribosyltransferase activity. PTX-B pretreatment also inhibited intracellular Ca2+ release by bradykinin and 2,4,6-trimethyl-N-( m -3-trifluoromethylphenyl) benzenesulfonamide ( m -3M3FBS), a director activator of phospholipase C. Activation of protein kinase C (PKC) by phorbol 12,13-dibutyrate (PdBu) mimicked the PTX-B-mediated inhibition of m -3M3FBS-stimulated intracellular Ca2+ increase, while inhibition of PKC by bisindolylmaleimide I hydrochloride (BIM) reversed the inhibitory action of PTX-B. Functionally, PTX-B reduced Tat-induced Bax and caspase-3 proteins and reduced cell apoptosis. We conclude that PTX inhibition of Tat-mediated intracellular Ca2+ release is independent of ADP ribosylation of the Gi protein via the A protomer, but mediated by the B-oligomer. Furthermore, PTX-B suppresses HIV-1 Tat-mediated apoptosis by reducing its activation of PLC-β through a PKC activation pathway. |
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ISSN: | 0306-4522 1873-7544 |
DOI: | 10.1016/j.neuroscience.2007.11.010 |