Cardiac glycosides ouabain and digoxin interfere with the regulation of glutamate transporter GLAST in astrocytes cultured from neonatal rat brain.
Glutamate transport (GluT) in brain is mediated chiefly by two transporters GLT and GLAST, both driven by ionic gradients generated by (Na(+), K(+))-dependent ATPase (Na(+)/K(+)-ATPase). GLAST is located in astrocytes and its function is regulated by translocations from cytoplasm to plasma membrane in the presence of GluT substrates. The phenomenon is blocked by a naturally occurring toxin rottlerin. We have recently suggested that rottlerin acts by inhibiting Na(+)/K(+)-ATPase. We now report that Na(+)/K(+)-ATPase inhibitors digoxin and ouabain also blocked the redistribution of GLAST in cultured astrocytes, however, neither of the compounds caused detectable inhibition of ATPase activity in cell-free astrocyte homogenates (rottlerin inhibited app. 80% of Pi production from ATP in the astrocyte homogenates, IC50 = 25 μM). Therefore, while we may not have established a direct link between GLAST regulation and Na(+)/K(+)-ATPase activity we have shown that both ouabain and digoxin can interfere with GluT transport and therefore should be considered potentially neurotoxic.
Nguyen
Khoa T D
KT
Discipline of Anatomy and Histology, School of Medical Sciences, Bosch Institute of Biomedical Research, Sydney Medical School, The University of Sydney, Anderson Stuart Building F 13, Sydney, NSW 2006, Australia.
Buljan
Vlado
V
Else
Paul L
PL
Pow
David V
DV
Balcar
Vladimir J
VJ
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004077:Digoxin / Q000494:pharmacology*; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D007150:Immunohistochemistry; D010042:Ouabain / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; C493392:Slc1a3 protein, rat; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase