Inositol 1,3,4,5-tetrakisphosphate as a mediator of neuronal death in ischemic hippocampus.
Selective death of CA1 pyramidal neurons after transient forebrain ischemia has attracted interest for its possible relation to the pathogenesis of memory deficits and dementia. Using whole cell patch-clamp recording from CA1 pyramidal neurons in hippocampal slices of gerbils after ischemia we studied the intracellular signaling mechanisms related to the phosphoinositide cycle. Intracellular application of an antibody against phosphatidylinositol 4,5-bisphosphate rescued ischemic neurons from stimulus-induced irreversible depolarization. Furthermore, application of inositol 1,3,4,5-tetrakisphosphate in normal cells caused an irreversible depolarization in response to synaptic input, which mimicked the deterioration of ischemic neurons. Depolarization of both ischemic and normal neurons in the presence of inositol 1,3,4,5-tetrakisphosphate was prevented by the addition of the Ca2+ chelator, 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetate. Application of antibody against inositol 1,4,5-triphosphate 3-kinase, which blocks formation of inositol 1,3,4,5-tetrakisphosphate, also protected against cell deterioration. Our results suggest that the vulnerability of hippocampal pyramidal neurons following ischemia is caused by a disturbed phosphoinositide cascade, with one metabolite, inositol 1,3,4,5-tetrakisphosphate, playing a key role in the induction of Ca2+ accumulation, which leads to neuronal death.
Tsubokawa
H
H
Department of Physiology, Jichi Medical School, Tochigi, Japan.
Oguro
K
K
Robinson
H P
HP
Masuzawa
T
T
Rhee
T S
TS
Takenawa
T
T
Kawai
N
N
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016923:Cell Death; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D005849:Gerbillinae; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007295:Inositol Phosphates / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D000906:Antibodies; D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D010716:Phosphatidylinositols; C081655:inositol-1,3,4,5-tetrakisphosphate; D004533:Egtazic Acid; D015544:Inositol 1,4,5-Trisphosphate; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid