Hypoxia stimulates Ca2+ release from intracellular stores in astrocytes via cyclic ADP ribose-mediated activation of ryanodine receptors

The ability of O-2 levels to regulate Ca2+ signalling in non-excitable cells is poorly understood, yet crucial to our understanding of Ca2+-dependent cell functions in physiological and pathological situations. Here, we demonstrate that hypoxia mobilizes U, from an intracellular pool in primary cultures of cortical astrocytes. This pool can also be mobilized by bradykinin, which acts via phospholipase C and inositol trisphosphate production. By contrast, hypoxic Ca2+ mobilization utilizes ryanodine receptors, which appear to be either present on the same intracellular pool. or on a separate but functionally coupled pool. Hypoxic activation of ryanodine receptors requires formation of cyclic ADP ribose, since hypoxic Ca2+ mobilization was fully prevented by nicotinamide (which inhibits ADP ribosyl cyclase) or by 8-Br-cADP ribose, an antagonist of cyclic ADP ribose. Our results demonstrate for the first time the involvement of cyclic ADP ribose in hypoxic modulation of Ca2+ signalling in the central nervous system, and suggest that this modulator of ryanodine receptors may play a key role in the function of astrocytes under conditions of fluctuating O-2 levels. (c) 2005 Elsevier Ltd. All rights reserved.