Modulation of L-type voltage-gated calcium channels by recombinant prion protein.
The prion protein (PrPC) has a primary role in the pathogenesis of transmissible spongiform encephalopathies. Here we analysed in detail the effect of recombinant PrPC and N- and C-terminal fragments of PrPC on the whole-cell current amplitude through voltage-gated calcium channels (VGCCs) of cultured wild-type cerebellar granule cells. With the application of full-length recombinant PrPC (50-500 nm), a highly significant reduction of the whole-cell current amplitude was observed in a dose-dependent manner. Amplitude reduction was abolished when cells were pre-incubated with nifedipine, a specific blocker of voltage-gated L-type calcium channels. N-terminal PrP fragments also led to a dose-dependent reduction of the maximal current amplitude, whereas a C-terminal fragment did not affect the current amplitude. These data demonstrate that nanomolar concentrations of PrPC modulate L-type VGCCs in mouse cerebellar granule cells, an effect that is dependent upon the copper-binding amino-terminal domain of PrPC.
Korte
Stefan
S
Department of Neuropathology, Ludwig-Maximilians-University München, München, Germany.
Vassallo
Neville
N
Kramer
Michael L
ML
Kretzschmar
Hans A
HA
Herms
Jochen
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003300:Copper / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017136:Ion Transport / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology
D020746:Calcium Channels, L-Type; D010446:Peptide Fragments; D018621:PrPC Proteins; D003300:Copper; C029892:cupric chloride; D002118:Calcium