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

Abstract

Prion diseases are neurodegenerative pathologies characterized by the accumulation, in the brain, of altered forms of the prion protein (PrP), named PrPSc. A synthetic peptide homologous to residues 106–126 of PrP (PrP106–126) was reported to maintain the neurodegenerative characteristics of PrPSc. 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 Ca2+ 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.

Keywords

• prion protein
• apoptosis
• L-type voltage-sensitive calcium channels
• nicardipine