Underestimation of the pentose-phosphate pathway in intact primary neurons as revealed by metabolic flux analysis

The rates of glucose oxidized at glycolysis and pentose-phosphate pathway (PPP) in neurons are controversial. Using [3-H-3]-, [1-C-14]-, and [6-C-14)glucose to estimate fluxes through these pathways in resting, intact rat cortical primary neurons, we found that the rate of glucose oxidized through PPP was, apparently, similar to 14% of total glucose metabolized. However, inhibition of PPP rate-limiting step, glucose-6-phosphate (G6P) dehydrogenase, increased approximately twofold the glycolytic rate; and, knockdown of phosphoglucose isomerase increased similar to 1.8-fold the PPP rate. Thus, in neurons, a considerable fraction of fructose-6-phosphate returning from the PPP contributes to the G6P pool that re-enters PPP, largely underestimating its flux.