Calbindin-D28k fails to protect hippocampal neurons against ischemia in spite of its cytoplasmic calcium buffering properties: evidence from calbindin-D28k knockout mice.
Cytoplasmic calcium-binding proteins are thought to shield neurons against damage induced by excessive Ca2+ elevations. Yet, in theory, a mobile cellular Ca2+ buffer could just as well promote neuronal injury by facilitating the rapid dispersion of Ca2+ throughout the cytoplasm. In sharp contrast to controls, in mice lacking the gene for calbindin-D28k, synaptic responses of hippocampal CA1 pyramidal neurons which are normally extremely vulnerable to ischemia, recovered significantly faster and more completely after a transient oxygen-glucose deprivation in vitro, and sustained less cellular damage following a 12 min carotid artery occlusion in vivo. Other cellular and synaptic properties such as the altered adaptation of action potential firing, and altered paired-pulse and frequency potentiation at affected synapses in calbindin-D28k-deficient mice were consistent with a missing intraneuronal Ca2+ buffer. Our findings provide direct experimental evidence against a neuroprotective role for calbindin-D28k.
Klapstein
G J
GJ
Department of Neurology, UCLA School of Medicine RNRC 3-131, Los Angeles, CA 90095-1769, USA.
Vietla
S
S
Lieberman
D N
DN
Gray
P A
PA
Airaksinen
M S
MS
Thoenen
H
H
Meyer
M
M
Mody
I
I
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D002021:Buffers; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000494:pharmacology*
D002021:Buffers; C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D064030:S100 Calcium Binding Protein G; D016202:N-Methylaspartate; D005947:Glucose; D010100:Oxygen; D002118:Calcium