L-beta-ODAP alters mitochondrial Ca2+ handling as an early event in excitotoxicity.
The neurotoxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (L-beta-ODAP) is an L-glutamate analogue at alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors in neurons and therefore acts as an excitotoxic substance. Chronic exposure to L-beta-ODAP present in Lathyrus sativus L. (L. sativus) seeds is proposed as the cause of the neurodegenerative disease neurolathyrism, but the mechanism of its action has not been conclusively identified. A key factor in excitotoxic neuronal cell death is a disturbance of the intracellular Ca2+ homeostasis, including changes in the capacity of intracellular Ca2+ stores like the endoplasmic reticulum (ER) or mitochondria. In this study, aequorin and other Ca2+ indicators were used in N2a neuroblastoma cells to investigate alterations of cellular Ca2+ handling after 24 h exposure to L-beta-ODAP. Our data demonstrate increased mitochondrial Ca2+ loading and hyperpolarization of the mitochondrial membrane potential (Psi(m)), which was specific for L-beta-ODAP and not observed with L-glutamate. We conclude that L-beta-ODAP disturbs the ER-mitochondrial Ca2+ signaling axis and thereby renders the cells more vulnerable to its excitotoxic effects that ultimately will lead to cell death.
Department of Basic Medical Sciences-Physiology Group, Faculty of Medicine and Health Sciences, De Pintelaan 185 (Block B, 3th Floor), Ghent University, B-9000 Ghent, Belgium.
Marijke
M
Van Moorhem
Elke
E
Decrock
Evelyne
E
Coussee
Liesbeth
L
Faes
Elke
E
De Vuyst
Katleen
K
Vranckx
Marijke
M
De Bock
Nan
N
Wang
Katharina
K
D'Herde
Fernand
F
Lambein
Geert
G
Callewaert
Luc
L
Leybaert
D000331:Aequorin; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007202:Indicators and Reagents; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D013997:Time Factors; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000633:toxicity
C510363:3-N-oxalyl-L -2,3-diaminopropanoic acid; D007202:Indicators and Reagents; D009498:Neurotoxins; D015091:beta-Alanine; D018698:Glutamic Acid; D000331:Aequorin; D002118:Calcium