Is autocrine ATP release required for activation of volume-sensitive chloride channels?

Abstract

We have also studied the role of ATP in activation of astrocytic VRACs, measured as release of preloaded [³H]labeled excitatory amino acid d-aspartate. We found that, in cultured astrocytes, exogenous 10 μM ATP activates a transient excitatory amino acid release in nonswollen cells and strongly potentiates amino acid release in hyposmotically swollen cells (Mongin and Kimelberg 2002; Fig. 1). This ATP-induced d-[³H]aspartate efflux was potently inhibited by the VRAC blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid, DIDS, and phloretin. It was also suppressed by a 10% increase in medium osmolarity (Mongin and Kimelberg 2002). On the basis of these data, we propose that ATP is incapable of direct VRAC activation, but instead, positively modulates a small fraction of VRACs that are active in nonswollen cells. The ATP-induced d-[³H]aspartate release in our experiments involving nonswollen cells did not exceed one-tenth of the release induced by a 100 mOsm reduction in medium osmolarity. In contrast, Darby and colleagues report a substantially higher activation of the Cl^– currents by ATP in nonswollen astrocytes, reaching one-half of the value of the hyposmotic Cl^– currents (Darby et al. 2003). If translated to ATP-induced VRAC-mediated glutamate release, such effect should have a large impact on normal brain physiology.