Regulation of AMPA receptor currents by mitochondrial ATP-sensitive K+ channels in anoxic turtle neurons.
Mammalian neurons rapidly undergo excitotoxic cell death during anoxia, whereas neurons from the anoxia-tolerant painted turtle survive without oxygen for hours and offer a unique model to study mechanisms to reduce the severity of cerebral stroke. An anoxia-mediated decrease in whole cell N-methyl-D-aspartate receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents are an important part of the turtle's natural defense. Here we investigate the role of mitochondrial ATP-sensitive K(+) (mK(ATP)) channels in the regulation of AMPAR. Whole cell AMPAR currents were stable over 90 min of normoxic recording; however, anoxia resulted in a 52% decrease in AMPAR currents. Pharmacological activation of mK(ATP) channels with diazoxide or levcromakalim resulted in a 46% decrease in normoxic AMPAR currents and the decrease was abolished with application of the antagonists 5-hydroxydecanoic acid and glibenclamide, whereas mK(ATP) antagonists blocked the anoxia-mediated decrease. Mitochondrial K(Ca) channel modulators responded similarly. The Ca(2+)-uniporter antagonist ruthenium red reduced AMPAR currents by 38% and was blocked with the agonist spermine. The calcium chelator BAPTA in the recording electrode during anoxia or diazoxide perfusion also abolished the reduction in AMPAR currents. We conclude that the mK(ATP) channel is involved in the anoxia-mediated down-regulation of AMPAR activity during anoxia and that it is a common mechanism to reduce glutamatergic excitability.
Zivkovic
George
G
University of Toronto, Department of Cell and Systems Biology, 25 Harbord Street, RW 329, Toronto, ON, Canada.
Buck
Leslie Thomas
LT
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D054086:KATP Channels / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009924:Organ Culture Techniques; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology; D014426:Turtles / Q000502:physiology*
D054086:KATP Channels; D018091:Receptors, AMPA