Principles of sodium homeostasis and sodium signalling in astroglia

Sodium homeostasis is at the center stage of astrocyte (and brain) physiology because the large inwardly directed Na(+) gradient provides the energy for transport of ions, neurotransmitters, amino acids and many other molecules across the plasmalemma and endomembranes. Cell imaging with commercially available chemical indicators allows analysis of dynamic changes in intracellular Na(+) concentration (Na(+) ]i ), albeit further technological developments, such as genetically-controlled or membrane targeted indicators or dyes usable for advanced microscopy (such as fluorescence-lifetime imaging microscopy) are urgently needed. Thus, important questions related to the existence of Na(+) gradients between different cellular compartments or occurrence of localised Na(+) micro/nanodomains at the plasma membrane remain debatable. Extrusion of Na(+) (and hence Na(+) homeostasis) in astrocytes is mediated by the ubiquitously expressed Na(+) /K(+) -ATPase (NKA), the major energy consumer of the brain. The activity of the NKA is counteracted by constant constitutive influx of Na(+) through transporters such as the NKCC1 (Na(+) -K(+) -2Cl(-) -co-transport) or the NBC (Na(+) -2 HCO3--co-transport). In addition, Na(+) -permeable ion channels at the plasma membrane as well as Na(+) -dependent solute carrier transporters provide for Na(+) influx into astrocytes. Activation of these pathways in response to neuronal activity results in an increase of [Na(+) ]i in astrocytes and there is manifold evidence for diverse signalling functions of these [Na(+) ]i transients. Thus, in addition to its established homeostatic functions, activity dependent fluctuations of astrocyte [Na(+) ]i regulate signalling cascades by feeding back on Na(+) -dependent transporters. The Na(+) signalling system may be ideally placed for fast coordinating signalling between neuronal activity and glial "homeostatic" Na(+) -dependent transporters. GLIA 2016;64:1611-1627.