Glutamine catabolism by heart muscle: regulation of phosphate-activated glutaminase by ATP, citrate, and chloride.
Production of glutamate from glutamine by rat heart mitochondria was stimulated by citrate and ATP in a dose-dependent manner. Citrate required phosphate for manifestation of its stimulatory action, whereas ATP enhanced glutaminase activity with and without phosphate. At low concentrations (1-50 mM) ATP was more potent than citrate, whereas the opposite was true at high (50-150 mM) levels of these anions. Both citrate and ATP decreased the concentration of phosphate required for half-maximal stimulation of glutamate production (EC50) and reduced the value of the Hill coefficient. Phosphate lowered the EC50 for ATP. Chloride and other anions of chaotropic series inhibited glutamine catabolism, most likely by causing depolymerization of the enzyme. Rupture of mitochondrial membranes by freeze-thawing decreased the responsiveness of glutaminase to phosphate, ATP, and especially to citrate but it did not alter the inhibition of the enzyme by chaotropic anions. It is concluded that phosphate, ATP, and citrate act in concert to modulate glutaminase activity in heart in vivo. Chloride, which exhibits a small inhibitory effect at a concentration normally present in cardiac muscle, may assume a greater regulatory role in situations accompanied by a rise in the internal level of this anion.
Nelson
D
D
Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104.
Rumsey
W L
WL
Erecińska
M
M
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000838:Anions; D001965:Bromides / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology*; D002951:Citrates / Q000494:pharmacology*; D005459:Fluorides / Q000494:pharmacology; D005972:Glutaminase / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000201:enzymology*; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D013861:Thiocyanates / Q000494:pharmacology
D000838:Anions; D001965:Bromides; D002712:Chlorides; D002951:Citrates; D013861:Thiocyanates; D005973:Glutamine; D000255:Adenosine Triphosphate; D005972:Glutaminase; D005459:Fluorides