Apoptotic cell death and impairment of L-type voltage-sensitive calcium channel activity in rat cerebellar granule cells treated with the prion protein fragment 106-126 |
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Authors: | Thellung S Florio T Villa V Corsaro A Arena S Amico C Robello M Salmona M Forloni G Bugiani O Tagliavini F Schettini G |
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Institution: | Dipartimento di Oncologia, Università di Genova, Servizio di Farmacologia e Neuroscienze Istituto Nazionale per la Ricerca sul Cancro (IST), Unità di Neuroscienze, Centro di Biotecnologie Avanzate (CBA), Genoa, I-16132, Italy. |
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Abstract: | Prion diseases are neurodegenerative pathologies characterized by the accumulation, in the brain, of altered forms of the prion protein (PrP), named PrP(Sc). A synthetic peptide homologous to residues 106-126 of PrP (PrP106-126) was reported to maintain the neurodegenerative characteristics of PrP(Sc). We investigated the intracellular mechanisms involved in PrP106-126-dependent degeneration of primary cultures of cerebellar granule neurons. Prolonged exposure of such neurons to PrP106-126 induced apoptotic cell death. The L-type voltage-sensitive calcium channel blocker nicardipine reproduced this effect, suggesting that blockade of Ca(2+) entry through this class of calcium channels may be responsible for the granule cell degeneration. Microfluorometric analysis showed that PrP106-126 caused a reduction in cytosolic calcium levels, elicited by depolarizing K(+) concentrations in these neurons. Electrophysiological studies demonstrated that PrP106-126 and nicardipine selectively reduce the L-type calcium channel current. These data demonstrate that PrP106-126 alters the activity of L-type voltage-sensitive calcium channels in rat cerebellar granule cells and suggest that this phenomenon is related to the cell death induced by the peptide. |
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