LAUSR

The maintenance of a low intracellular sodium concentration by the Na+/K+‐ATPase (NKA) is critical for brain function. In both neurons and glial cells, NKA activity is required to counteract changes in the sodium gradient due to opening of voltage‐ and ligand‐gated channels and/or activation of sodium‐dependent secondary active transporters. Because NKA consumes about 50% of cellular ATP, sodium homeostasis is strictly dependent on an intact cellular energy metabolism. Despite the high energetic costs of electrical signaling, neurons do not contain significant energy stores themselves, but rely on a close metabolic interaction with surrounding astrocytes. A disruption of energy supply as observed during focal ischemia causes a rapid drop in ATP in both neurons and astrocytes. There is accumulating evidence that dysregulation of intracellular sodium is an inherent consequence of a reduction in cellular ATP, triggering secondary failure of extra‐ and intracellular homeostasis of other ions ‐in particular potassium, calcium, and protons‐ and thereby promoting excitotoxicity. The characteristics, cellular mechanisms and direct consequences of harmful sodium influx, however, differ between neurons and astrocytes. Moreover, recent work has shown that an intact astrocyte metabolism and sodium homeostasis are critical to maintain the sodium homeostasis of surrounding neurons as well as their capacity to recover from imposed sodium influx. Understanding the mechanisms of sodium increases upon metabolic failure and the differential responses of neurons and glial cells as well as their metabolic interactions will be critical to fully unravel the events causing cellular malfunction, failure and cell death following energy depletion. © 2017 Wiley Periodicals, Inc.