INTRACELLULAR CALCIUM RISE THROUGH L-TYPE CALCIUM CHANNELS, AS MOLECULAR MECHANISM FOR PRION PROTEIN-FRAGMENT 106-126-INDUCED ASTROGLIAL PROLIFERATION

The infectious prion protein (PrPSc) is the etiologic agent of transmi ssible neurodegenerative conditions such as scrapie or Creutzfeldt-Jak ob disease. Its fragment 106-126 (PrP106-126) has been reported to mai ntain most of the pathological features of PrPSc. We report here the i ntracellular mechanisms mediating the proliferative effects of PrP106- 126 on rat cortical type I astrocytes. The proliferative effects of Pr P106-126 started after 24h of treatment and lasted up to 9 days and wa s antagonized by the L-type voltage-sensitive calcium channel blocker nicardipine. Microfluorimetric studies showed that PrP106-126 caused a rapid increase in the [Ca++](i). This effect was prevented by nicardi pine, or by Ca++-free conditions, showing that the PrP106-126 enhances [Ca++](i) mobilizing Ca++ from the extracellular environment. Moreove r, binding studies demonstrated a direct interference of PrP106-126 wi th the dihydropyridine binding site. This is the first evidence that a prion protein fragment directly stimulates the proliferation of astro cytes via an increase in [Ca++](i) through the L-type voltage-sensitiv e calcium channels. (C) 1996 Academic Press, Inc.