Alterations in Ca2+-buffering in prion-null mice: association with reduced afterhyperpolarizations in CA1 hippocampal neurons.
Prion protein (PrP) is a normal component of neurons, which confers susceptibility to prion diseases. Despite its evolutionary conservation, its normal function remains controversial. PrP-deficient (Prnp(0/0)) mice have weaker afterhyperpolarizations (AHPs) in cerebellar and hippocampal neurons. Here we show that the AHP impairment in hippocampal CA1 pyramidal cells is selective for the slow AHP, and is not caused by an impairment of either voltage-gated Ca(2+) channels or Ca(2+)-activated K(+) channels. Instead, Prnp(0/0) neurons have twofold to threefold stronger Ca(2+) buffering and double the Ca(2+) extrusion rate. In Prnp(0/0) neurons thapsigargin abolished the stronger Ca(2+) buffering and extrusion, and thapsigargin or cyclopiazonic acid abolished the weakening of the slow AHPs. These data implicate sarcoplasmic/endoplasmic reticulum calcium ATPase in the enhanced Ca(2+) buffering, and extrusion into the endoplasmic reticulum, which contains substantial amounts of PrP in wild-type mice. Altered Ca(2+) homeostasis can explain several phenotypes identified in Prnp(0/0) mice.
Powell
Andrew D
AD
Division of Neuroscience (Neurophysiology), The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
Toescu
Emil C
EC
Collinge
John
J
Jefferys
John G R
JG
D000200:Action Potentials; D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010782:Photolysis; D011257:Pregnancy Proteins / Q000172:deficiency*; D017966:Pyramidal Cells; D011930:Reaction Time; D019284:Thapsigargin / Q000494:pharmacology
D002021:Buffers; D004791:Enzyme Inhibitors; D007211:Indoles; C057074:Plfr protein, mouse; D011257:Pregnancy Proteins; D019284:Thapsigargin; D002118:Calcium; C000543:cyclopiazonic acid