Plasmalemmal Na(+)/Ca(2+) exchanger modulates Ca(2+)-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).