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 transmissible neurodegenerative conditions such as scrapie or Creutzfeldt-Jakob disease. Its fragment 106-126 (PrP106-126) has been reported to maintain most of the pathological features of PrPSc. We report here the intracellular mechanisms mediating the proliferative effects of PrP106-126 on rat cortical type I astrocytes. The proliferative effects of PrP106-126 started after 24h of treatment and lasted up to 9 days and was antagonized by the L-type voltage-sensitive calcium channel blocker nicardipine. Microfluorimetric studies showed that PrP106-126 caused a rapid increase in the [Ca+2]i. This effect was prevented by nicardipine, or by Ca(+2)-free conditions, showing that the PrP106-126 enhances [Ca+2]i mobilizing Ca+2 from the extracellular environment. Moreover, binding studies demonstrated a direct interference of PrP106-126 with the dihydropyridine binding site. This is the first evidence that a prion protein fragment directly stimulates the proliferation of astrocytes via an increase in [Ca+2]i through the L-type voltage-sensitive calcium channels.
Florio
T
T
Istituto di Farmacologia, Facoltà di Medicina, Università di Genova, Italy.
Grimaldi
M
M
Scorziello
A
A
Salmona
M
M
Bugiani
O
O
Tagliavini
F
F
Forloni
G
G
Schettini
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004247:DNA / Q000096:biosynthesis; D017275:Isradipine / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D009529:Nicardipine / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011328:Prions / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; C082632:prion protein (106-126); D004247:DNA; D009529:Nicardipine; D002118:Calcium; D013936:Thymidine; D017275:Isradipine