Ionic mechanisms of action of prion protein fragment PrP(106-126) in rat basal forebrain neurons.
Prion diseases are neurodegenerative disorders that are characterized by the presence of the misfolded prion protein (PrP). Neurotoxicity in these diseases may result from prion-induced modulation of ion channel function, changes in neuronal excitability, and consequent disruption of cellular homeostasis. We therefore examined PrP effects on a suite of potassium (K(+)) conductances that govern excitability of basal forebrain neurons. Our study examined the effects of a PrP fragment [PrP(106-126), 50 nM] on rat neurons using the patch clamp technique. In this paradigm, PrP(106-126) peptide, but not the "scrambled" sequence of PrP(106-126), evoked a reduction of whole-cell outward currents in a voltage range between -30 and +30 mV. Reduction of whole-cell outward currents was significantly attenuated in Ca(2+)-free external media and also in the presence of iberiotoxin, a blocker of calcium-activated potassium conductance. PrP(106-126) application also evoked a depression of the delayed rectifier (I(K)) and transient outward (I(A)) potassium currents. By using single cell RT-PCR, we identified the presence of two neuronal chemical phenotypes, GABAergic and cholinergic, in cells from which we recorded. Furthermore, cholinergic and GABAergic neurons were shown to express K(v)4.2 channels. Our data establish that the central region of PrP, defined by the PrP(106-126) peptide used at nanomolar concentrations, induces a reduction of specific K(+) channel conductances in basal forebrain neurons. These findings suggest novel links between PrP signalling partners inferred from genetic experiments, K(+) channels, and PrP-mediated neurotoxicity.
Alier
Kwai
K
Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta, Canada.
Li
Zongming
Z
Mactavish
David
D
Westaway
David
D
Jhamandas
Jack H
JH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002491:Central Nervous System Agents; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002491:Central Nervous System Agents; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; C082632:prion protein (106-126); C064719:iberiotoxin; D011188:Potassium; D002118:Calcium