Effect of insulin-induced hypoglycemia on cytoskeleton-bound and cytosolic phosphofructokinase and the levels of glucose 1,6-bisphosphate in rat brain.
We investigated the regulatory mechanisms which may account for the reduction of glycolysis in brain during severe hypoglycemia. Phosphofructokinase (PFK), the rate-limiting enzyme in glycolysis, is known to be regulated by allosteric effectors, as well as by a reversible binding to cell cytoskeleton. These two mechanisms were studied, in rat brain, during insulin-induced hypoglycemia. Our experiments revealed that the intracellular distribution of PFK was not changed during severe hypoglycemia. However, the allosteric activity of the enzyme (assayed under conditions in which it is sensitive to allosteric effectors) from both the cytosolic (soluble) and cytoskeletal fractions, was significantly reduced. This reduction may be attributed to the marked fall in the level of glucose 1,6-bisphosphate (Glc-1,6-P2), the potent allosteric activator of PFK, as well as to the more moderate decrease in fructose 2,6-bisphosphate and the decrease in fructose 1,6-bisphosphate (the product and allosteric activator of the enzyme). In contrast to our previous findings in muscle, the cytoskeleton-bound PFK from brain was found to be sensitive to allosteric effectors like the soluble enzyme. This may explain the reduction in the allosteric activity of PFK in both the cytosolic and cytoskeletal fractions from brain. The decline in cytoskeleton-bound and cytosolic PFK activity, induced by the fall in its allosteric activators, may lead to the reduction in brain glycolytic rate, which was reflected by the marked decrease in lactate content during hypoglycemia.
Magen
A
A
Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Koren-Schwartzer
N
N
Chen-Zion
M
M
Beitner
R
R
D000494:Allosteric Regulation; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D003599:Cytoskeleton / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives* / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced*; D007328:Insulin / Q000494:pharmacology*; D010732:Phosphofructokinase-1 / Q000378:metabolism*; D051381:Rats
D007328:Insulin; D019298:Glucose-6-Phosphate; C016473:glucose-1,6-bisphosphate; D010732:Phosphofructokinase-1