Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage.
Na+/Ca+ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na+ and Ca2+ homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3-/- mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3-/- mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3-/- mice exposed to OGD plus reoxygenation. In addition, in ncx3-/- cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.
Molinaro
Pasquale
P
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, 80131 Naples, Italy.
Cuomo
Ornella
O
Pignataro
Giuseppe
G
Boscia
Francesca
F
Sirabella
Rossana
R
Pannaccione
Anna
A
Secondo
Agnese
A
Scorziello
Antonella
A
Adornetto
Annagrazia
A
Gala
Rosaria
R
Viggiano
Davide
D
Sokolow
Sophie
S
Herchuelz
Andre
A
Schurmans
Stèphane
S
Di Renzo
Gianfranco
G
Annunziato
Lucio
L
D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D018390:Gene Targeting / Q000379:methods*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009924:Organ Culture Techniques; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000235:genetics*
D026901:Membrane Transport Proteins; C491101:Slc8a3 protein, mouse; D019831:Sodium-Calcium Exchanger