An inflammatory mediator, bradykinin, is known to induce glutamate release from astrocytes in the brain, providing a way of astrocyte-neuron signalling during brain inflammation. Here we report that this bradykinin-induced signalling is mediated by volume-sensitive outwardly rectifying (VSOR) anion channels on mouse cortical astrocytes in the absence of significant cell volume changes. Glutamate release from astrocytes induced by bradykinin (1 μM) evoked [Ca2+]i rises through NMDA receptor activation in adjacent neurons in co-culture, and these [Ca2+]i rises were blocked by an anion channel blocker, DIDS (200 μM) or phloretin (100 μM). Glutamate assay indicated that the amount of released glutamate was indeed reduced by these blockers or hypertonic stimuli, but the amount was not affected by an exocytosis blocker, tetanus toxin A (1 μg ⁄ ml for 24 hrs). Application of bradykinin activated concurrently the whole-cell anion current through VSOR in astrocytes. This VSOR activation, however, was not accompanied by cell volume changes, but associated with generation of intracellular reactive oxygen species (ROS), which was confirmed by the inhibition of VSOR activation with a ROS scavenger (10 mM NAC) or a ROS-generating NADPH oxidase (NOX) inhibitor (10 μM DPI). These indicate that bradykinin-induced astrocyte-neuron signalling is mediated by glutamate release via ROS-activated VSOR anion channels. This would provide a pathophysiological basis for the neuronal hyperactivity, swelling and edema during brain inflammation.
Liu HT, Akita T, Shimizu T, Sabirov RZ, and Okada Y (2009) Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels. J. Physiol. published online on February 2, DOI: 10.1113⁄jphysiol.2008.165084
