Activity-dependent adenosine release may be linked to activation of Na(+)-K(+) ATPase: an in vitro rat study.
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 Ca(2+), 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.
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Robert Edward
RE
Sims
School of Life Sciences, University of Warwick, Coventry, United Kingdom.
Nicholas
N
Dale
D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D066298:In Vitro Techniques; D008297:Male; D009044:Motor Cortex / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018091:Receptors, AMPA; D010042:Ouabain; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000254:Sodium-Potassium-Exchanging ATPase; D000241:Adenosine