Abstract
BACKGROUND: The central clock of the suprachiasmatic nucleus (SCN) controls the metabolism of glucose and is sensitive to glucose shortage. However, it is only beginning to be understood how metabolic signals such as glucose availability regulate the SCN physiology. We previously showed that the ATP-sensitive K(+) channel plays a glucose-sensing role in regulating SCN neuronal firing at times of glucose shortage. Nevertheless, it is unknown whether the energy-demanding Na(+)/K(+)-ATPase (NKA) is also sensitive to glucose availability. Furthermore, we recently showed that the metabolically active SCN constantly extrudes H(+) to acidify extracellular pH (pHe). This study investigated whether the standing acidification is associated with Na(+) pumping activity, energy metabolism, and glucose utilization, and whether glycolysis- and mitochondria-fueled NKAs may be differentially sensitive to glucose shortage. METHODS: Double-barreled pH-selective microelectrodes were used to determine the pHe in the SCN in hypothalamic slices. RESULTS: NKA inhibition with K(+)-free (0-K(+)) solution rapidly and reversibly alkalinized the pHe, an effect abolished by ouabain. Mitochondrial inhibition with cyanide acidified the pHe but did not inhibit 0-K(+)-induced alkalinization. Glycolytic inhibition with iodoacetate alkalinized the pHe, completely blocked cyanide-induced acidification, and nearly completely blocked 0-K(+)-induced alkalinization. The results indicate that glycolytic metabolism and activation of Na(+) pumping contribute to the standing acidification. Glucoprivation also alkalinized the pHe, nearly completely eliminated cyanide-induced acidification, but only partially reduced 0-K(+)-induced alkalinization. In contrast, hypoglycemia preferentially and partially blocked cyanide-induced acidification. The result indicates sensitivity to glucose shortage for the mitochondria-associated oxidative glycolytic pathway. CONCLUSION: Glycolytic metabolism and activation of glycolysis-fueled NKA Na(+) pumping activity contribute to the standing acidification in the SCN. Furthermore, the oxidative and non-oxidative glycolytic pathways differ in their glucose sensitivity and utilization, with the oxidative glycolytic pathway susceptible to glucose shortage, and the non-oxidative glycolytic pathway able to maintain Na(+) pumping even in glucoprivation.