Extracellular Na+ levels regulate formation and activity of the NaX/alpha 1-Na+/K+-ATPase complex in neuronal cells

MnPO neurons play a critical role in hydromineral homeostasis regulation by acting as sensors of extracellular sodium concentration ([Na+](out)). The mechanism underlying Na+-sensing involves Na+-flow through the Na-X channel, directly regulated by the Na+/K+-ATPase alpha 1-isoform which controls Na+-influx by modulating channel permeability. Together, these two partners form a complex involved in the regulation of intracellular sodium ([Na+](in)). Here we aim to determine whether environmental changes in Na+ could actively modulate the Na-X/Na+/K+-ATPase complex activity. We investigated the complex activity using patch-clamp recordings from rat MnPO neurons and Neuro2a cells. When the rats were fed with a high-salt-diet, or the [Na+] in the culture medium was increased, the activity of the complex was up-regulated. In contrast, drop in environmental [Na+] decreased the activity of the complex. Interestingly under hypernatremic condition, the colocalization rate and protein level of both partners were up-regulated. Under hyponatremic condition, only Na-X protein expression was increased and the level of Na-X/Na+/K+-ATPase remained unaltered. This unbalance between Na-X and Na+/K+-ATPase pump proportion would induce a bigger portion of Na+/K+-ATPase-control-free Na-X channel. Thus, we suggest that hypernatremic environment increases Na-X/Na+/K+-ATPase alpha 1-isoform activity by increasing the number of both partners and their colocalization rate, whereas hyponatremic environment down-regulates complex activity via a decrease in the relative number of Na-X channels controlled by the pump.