We have previously demonstrated that rat cerebellar Type‐1 astrocytes express a very active genistein sensitive Na⁺/Ca²⁺exchanger, which accounts for most of the total plasma membrane Ca²⁺fluxes and for the clearance ofloads induced by physiological agonists. In this work, we have explored the mechanism by which the reverse Na⁺/Ca²⁺exchange is involved in agonist‐induced Ca²⁺signaling in rat cerebellar astrocytes. Microspectrofluorometric measurements ofwith Fluo‐3 demonstrate that thesignals associated long (> 20 s) periods of reverse operation of the Na⁺/Ca²⁺exchange are amplified by a mechanism compatible with calcium‐calcium release, while those associated with short (< 20 s) pulses are not amplified. This was confirmed by pharmacological experiments using ryanodine receptors agonist (4‐chloro‐m‐cresol) and the endoplasmic reticulum ATPase inhibitor (thapsigargin). Confocal microscopy demonstrates a high co‐localization of immunofluorescent labeled Na⁺/Ca²⁺exchanger and RyRs. Low (< 50 μmol/L) or high (> 500 μmol/L) concentrations ofl‐glutamate (l‐Glu) orl‐aspartate causes a rise inwhich is completely blocked by the Na⁺/Ca²⁺exchange inhibitors KB‐R7943 and SEA0400. The most important novel finding presented in this work is thatl‐Glu activates the reverse mode of the Na⁺/Ca²⁺exchange by inducing Na⁺entry through the electrogenic Na⁺–Glu‐co‐transporter and not through the ionophoricl‐Glu receptors, as confirmed by pharmacological experiments with specific blockers of the ionophoricl‐Glu receptors and the electrogenic Glu transporter.

Because firing properties and metabolic rates vary widely, neurons require different transport rates from their Na⁺/K⁺ pumps in order to maintain ion homeostasis. In this study we show that Na⁺/K⁺ pump activity is tightly regulated by a novel process, RNA editing. Three codons within the squid Na⁺/K⁺ ATPase gene can be recoded at the RNA level, and the efficiency of conversion for each varies dramatically, and independently, between tissues. At one site, a highly conserved isoleucine in the seventh transmembrane span can be converted to a valine, a change that shifts the pump's intrinsic voltage dependence. Mechanistically, the removal of a single methyl group specifically targets the process of Na⁺ release to the extracellular solution, causing a higher turnover rate at the resting membrane potential. In order for excitable cells like neurons and muscles to generate electrical signals, they require ion gradients across their plasma membranes. For example, sodium concentrations are much lower inside a cell than outside, and for potassium it is the opposite case. The job of maintaining these ion gradients falls squarely on a single protein: the Na⁺/K⁺ pump. During each transport cycle, this enzyme moves three sodium ions out of the cell and imports two of potassium. Because this process is the foundation for so many physiological processes, the Na⁺/K⁺ pump is costly to operate, using ∼30% of the ATP generated by an organism. Proper regulation of its turnover rate is vital. In this work, we use the giant nerve cell of squid as a model to show that the Na⁺/K⁺ pump can be regulated by an unsuspected mechanism. Although the gene that codes for this enzyme can make a perfectly functional pump, sometimes its information changes as it passes through the messenger RNA. This is achieved by editing RNA and as a result subtly different versions of the pump can be made, differing at only three amino acids out of more than a thousand. We demonstrate that RNA editing modulates the Na⁺/K⁺ pump's turnover rate and sodium release.