Plasmalemmal Na/Ca Exchanger Modulates Ca-Dependent Exocytotic Release of Glutamate from Rat Cortical Astrocytes

Astroglial excitability operates through increases in Ca 2+ cyt (cytosolic Ca 2+ ), which can lead to glutamatergic gliotransmission. In parallel fluctuations in astrocytic Na + cyt (cytosolic Na + ) control metabolic neuronal-glial signalling, most notably through stimulation of lactate production, which on release from astrocytes can be taken up and utilized by nearby neurons, a process referred to as lactate shuttle. Both gliotransmission and lactate shuttle play a role in modulation of synaptic transmission and plasticity. Consequently, we studied the role of the PMCA (plasma membrane Ca 2+ -ATPase), NCX (plasma membrane Na + /Ca 2+ exchanger) and NKA (Na + /K + -ATPase) in complex and coordinated regulation of Ca 2+ cyt and Na + cyt in astrocytes at rest and upon mechanical stimulation. Our data support the notion that NKA and PMCA are the major Na + and Ca 2+ extruders in resting astrocytes. Surprisingly, the blockade of NKA or PMCA appeared less important during times of Ca 2+ and Na + cytosolic loads caused by mechanical stimulation. Unexpectedly, NCX in reverse mode appeared as a major contributor to overall Ca 2+ and Na + homoeostasis in astrocytes both at rest and when these glial cells were mechanically stimulated. In addition, NCX facilitated mechanically induced Ca 2+ -dependent exocytotic release of glutamate from astrocytes. These findings help better understanding of astrocyte-neuron bidirectional signalling at the tripartite synapse and/or microvasculature. We propose that NCX operating in reverse mode could be involved in fast and spatially localized Ca 2+ -dependent gliotransmission, that would operate in parallel to a slower and more widely distributed gliotransmission pathway that requires metabotropically controlled Ca 2+ release from the ER (endoplasmic reticulum).