Abstract
In the brain, extracellular adenosine increases as a result of neuronal activity. The mechanisms by which this occurs are only incompletely understood. Here we investigate the hypothesis that the Na+ influxes associated with neuronal signalling activate the Na+-K+ ATPase which, by consuming ATP, generates intracellular adenosine that is then released via transporters. By measuring adenosine release directly with microelectrode biosensors, we have demonstrated that AMPA-receptor evoked adenosine release in basal forebrain and cortex depends on extracellular Na+. We have simultaneously imaged intracellular Na+ and measured adenosine release. The accumulation of intracellular Na+ during AMPA receptor activation preceded adenosine release by some 90 s. By removing extracellular Ca2+, and thus preventing indiscriminate neuronal activation, we used ouabain to test the role of the Na+-K+ ATPase in the release of adenosine. Under conditions which caused a Na+ influx, brief applications of ouabain increased the accumulation of intracellular Na+ but conversely rapidly reduced extracellular adenosine levels. In addition, ouabain greatly reduced the amount of adenosine released during application of AMPA. Our data therefore suggest that activity of the Na+-K+ ATPase is directly linked to the efflux of adenosine and could provide a universal mechanism that couples adenosine release to neuronal activity. The Na+-K+ ATPase-dependent adenosine efflux is likely to provide adenosine-mediated activity-dependent negative feedback that will be important in many diverse functional contexts including the regulation of sleep.
Highlights
Adenosine is perhaps the most pervasive modulator in the brain, where it can act at a number of G-protein coupled receptors [1] to modulate neuronal and network activity [2,3,4,5]
We have previously shown that certain depolarizing stimuli, most notably activation of AMPA (2-amino-3-(3-hydroxy-5methyl-isoxazol-4-yl)propanoic acid) receptors, reliably evoke adenosine release in the basal forebrain (BFB) and cortex [19]
The AMPA-evoked adenosine release was sensitive to TTX, which substantially, but not completely (.60% block), inhibited adenosine release in both BFB and cortex evoked by AMPA and high K+ (Fig 2D–F)
Summary
Adenosine is perhaps the most pervasive modulator in the brain, where it can act at a number of G-protein coupled receptors [1] to modulate neuronal and network activity [2,3,4,5]. It is increasingly apparent that the extracellular concentration of adenosine can be increased as a result of neural activity, allowing adenosine to mediate state-dependent actions that depend on prior activity in the nervous system [7,8,9,10,11,12,13]. Some of this adenosine arises from prior release of ATP from astrocytes. In the cerebellum this arises from exocytosis, but in other brain regions, such as hippocampus and cortex, direct activitydependent release of adenosine appears to be mediated via facilitative transporters [12]
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