On the special role of NCX in astrocytes: Translating Na+-transients into intracellular Ca2+ signals

• Published in: Cell calcium (Edinburgh) 2020-03, Vol.86, p.102154-102154, Article 102154
• Main Authors: Rose, Christine R., Ziemens, Daniel, Verkhratsky, Alexei
• Format: Article
• Language: English
• Subjects: Astroglial ionic excitability; Calcium; Neurone-glia interaction; Sodium; Synapse
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2019.102154

NCX couples the plasma membrane gradients of sodium and calcium ions (Na+, Ca2+) to the membrane potential of astrocytes. Activity-related intracellular Na+ transients result in a switch from forward into reverse mode, thereby generating astrocytic Ca2+ signals. [Display omitted] •Astrocytes express all three isoforms of the sodium/calcium exchanger (NCX).•NCX is preferentially located on perisynaptic processes and endfeet and contributes to regulation of baseline Na+ and Ca2+.•In physiological conditions, NCX transport direction fluctuates between forward and reverse mode.•Activity-induced transient increases in astrocyte Na+ drive the NCX into reverse mode, producing astrocytic Ca2+ signals.•Na+-driven Ca2+ signals generated by reverse NCX serve important functional roles in neurone-glia interaction. As a solute carrier electrogenic transporter, the sodium/calcium exchanger (NCX1-3/SLC8A1-A3) links the trans-plasmalemmal gradients of sodium and calcium ions (Na+, Ca2+) to the membrane potential of astrocytes. Classically, NCX is considered to serve the export of Ca2+ at the expense of the Na+ gradient, defined as a “forward mode” operation. Forward mode NCX activity contributes to Ca2+ extrusion and thus to the recovery from intracellular Ca2+ signals in astrocytes. The reversal potential of the NCX, owing to its transport stoichiometry of 3 Na+ to 1 Ca2+, is, however, close to the astrocytes’ membrane potential and hence even small elevations in the astrocytic Na+ concentration or minor depolarisations switch it into the “reverse mode” (Ca2+ import/Na+ export). Notably, transient Na+ elevations in the millimolar range are induced by uptake of glutamate or GABA into astrocytes and/or by the opening of Na+-permeable ion channels in response to neuronal activity. Activity-related Na+ transients result in NCX reversal, which mediates Ca2+ influx from the extracellular space, thereby generating astrocyte Ca2+ signalling independent from InsP3-mediated release from intracellular stores. Under pathological conditions, reverse NCX promotes cytosolic Ca2+ overload, while dampening Na+ elevations of astrocytes. This review provides an overview on our current knowledge about this fascinating transporter and its special functional role in astrocytes. We shall delineate that Na+-driven, reverse NCX-mediated astrocyte Ca2+ signals are involved neurone-glia interaction. Na+ transients, translated by the NCX into Ca2+ elevations, thereby emerge as a new signalling path