Prion protein affects Ca2+-activated K+ currents in cerebellar purkinje cells.
The prion protein (PrPC) has a primary role in the pathogenesis of transmissible spongiform encephalopathies. Its physiological function is not known yet. Altered late afterhyperpolarization has been observed in hippocampal CA1 pyramidal cells of prion protein-deficient mice (Prnp(0/0) mice) presumably caused by a disruption of Ca2+-activated K+ currents. An alteration of these currents has been recently described in scrapie-infected animals, and loss of function of PrPC has been put forward as one possible pathophysiological mechanism in prion diseases. This work focuses on patch-clamp studies of Ca2+-activated K+ currents in cerebellar Purkinje cells in the slice preparation of Prnp(0/0) mice as well as of transgenic mice. A significant correlation between PrPC expression in Purkinje cells and the maximal amplitude of TEA-insensitive Ca2+-activated K+ currents was observed, with reduced current amplitudes in Prnp(0/0) mice and a rescue of the phenotype in transgenic mice where PrPC had been reintroduced. Further studies of the intracellular free calcium concentration revealed an alteration of the maximal increase of intracellular calcium concentration with depolarization in the Prnp(0/0) mouse Purkinje cells. These data provide strong evidence that Ca2+-activated K+ currents in Prnp(0/0) mice are reduced due to an alteration of intracellular calcium homeostasis.
Herms
J W
JW
Department of Neuropathology, Georg-August Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, 37075, Germany.
Tings
T
T
Dunker
S
S
Kretzschmar
H A
HA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D016257:Fura-2 / Q000493:pharmacokinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D018621:PrPC Proteins / Q000378:metabolism / Q000494:pharmacology*; D017096:Prion Diseases / Q000378:metabolism / Q000503:physiopathology; D011689:Purkinje Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D005456:Fluorescent Dyes; D015221:Potassium Channels; D018621:PrPC Proteins; D002118:Calcium; D016257:Fura-2