NBCe1 Mediates the Acute Stimulation of Astrocytic Glycolysis by Extracellular K+

Excitatory synaptic transmission stimulates brain tissue glycolysis. This phenomenon is the signal detected in FDG-PET imaging and, through enhanced lactate production, is also thought to contribute to the fMRI signal. Using a method based on Forster resonance energy transfer in mouse astrocytes, we have recently observed that a small rise in extracellular K (+) can stimulate glycolysis by > 300% within seconds. The K (+) response was blocked by ouabain, but intracellular engagement of the Na (+)/K (+) ATPase pump with Na (+) was ineffective, suggesting that the canonical feedback regulatory pathway involving the Na (+) pump and ATP depletion is only permissive and that a second mechanism is involved. Because of their predominant K (+) permeability and high expression of the electrogenic Na (+)/HCO3- cotransporter NBCe1, astrocytes respond to a rise in extracellular K (+) with plasma membrane depolarization and intracellular alkalinization. In the present article, we show that a fast glycolytic response can be elicited independently of K (+) by plasma membrane depolarization or by intracellular alkalinization. The glycolytic response to K (+) was absent in astrocytes from NBCe1 null mice (Slc4a4) and was blocked by functional or pharmacological inhibition of the NBCe1. Hippocampal neurons acquired K (+) -sensitive glycolysis upon heterologous NBCe1 expression. The phenomenon could also be reconstituted in HEK293 cells by coexpression of the NBCe1 and a constitutively open K (+) channel. We conclude that the NBCe1 is a key element in a feedforward mechanism linking excitatory synaptic transmission to fast modulation of glycolysis in astrocytes.