The role of cytosolic free calcium in the regulation of pyruvate dehydrogenase in synaptosomes.
Calcium homeostasis and mitochondrial oxidative metabolism interact closely in brain and both processes are impaired during hypoxia. Since the regulation of the pyruvate dehydrogenase complex (PDHC) may link these two processes, the relation of cytosolic free calcium ([Ca2+]i) to the activation state of PDHC (PDHa) was assessed in isolated nerve terminals (i.e. synaptosomes) under conditions that alter [Ca2+]i. K+ depolarization elevated [Ca2+]i and PDHa and both responses required external calcium. Treatment with KCN, an in vitro model of hypoxia decreased ATP and elevated [Ca2+]i and PDHa. Furthermore, in the presence of KCN, PDHa became more sensitive to K+ depolarization as indicated by larger changes in PDHa than in [Ca2+]i. The calcium ionophore Br-A23187 elevated [Ca2+]i, but did not affect PDHa. K+ depolarization elevated [Ca2+]i and PDHa even if [Ca2+]i was elevated by prior addition of ionophore or KCN. Previous in vivo studies by others show that PDHa is altered during and after ischemia. The current in vitro results suggest that hypoxia, only one component of ischemia, is sufficient to increase PDHa. These data also further support the notion that PDHa is regulated by [Ca2+]i as well as by other factors such as ATP. Our results are consistent with the concept that PDHa in nerve endings may be affected by [Ca2+]i and that these two processes are clearly linked.
Huang
H M
HM
Department of Neurology and Neuroscience, Cornell University Medical College, Burke Medical Research Institute, White Plains, New York 10605.
Toral-Barza
L
L
Sheu
K F
KF
Gibson
G E
GE
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation; D006706:Homeostasis; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D011189:Potassium Chloride / Q000494:pharmacology; D011190:Potassium Cyanide / Q000494:pharmacology; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology
D011768:Pyruvate Dehydrogenase Complex; D000001:Calcimycin; D004533:Egtazic Acid; D011189:Potassium Chloride; D011190:Potassium Cyanide; D002118:Calcium