Astrocytes are in intimate contact with neurons, in particular with synapses, and are able to sense, react to, and even influence neuronal activity. The astrocytic response to neuronal activity can be most readily detected by observing changes in the intracellular Ca 2ϩ concentration mediated via transmitter receptors (e.g. glutamate, GABA (␥-aminobutyric acid), or acetylcholine) or via other messengers, such as nitric oxide. Ca 2ϩ increases can occur by Ca 2ϩ influx via the plasma membrane as found for the nitric oxide-mediated neuron-glia signaling in the cerebellum (1). Ca 2ϩ can furthermore be released from intracellular stores by activation of metabotropic receptors such as GABA B receptors, which mediate neuron-glia signaling in the hippocampus (2). Indeed, astrocytes express a variety of receptors linked to the Ca 2ϩ mobilization from intracellular stores (3). To produce specific signals with one and the same messenger (Ca 2ϩ ), several second messenger pathways and different sources of Ca 2ϩ are involved. It seems important, at the current stage, to decipher the astrocytic Ca 2ϩ code, since this would lead to further understanding of how these cells can react to and influence the neuronal network.The best investigated second messenger linking activation of metabotropic receptors and Ca 2ϩ release is inositol 1,4,5-trisphosphate (IP 3 ). 2The importance of other intracellular messengers, such as cyclic ADPribose (cADPR), is less well understood (4) or still hypothetical as for the two sphingomyelin metabolites sphingosine 1-phosphate (5) and sphingosylphosphorylcholine (6). Almost a decade ago, a novel intracellular Ca 2ϩ -releasing second messenger was identified in sea urchin eggs, nicotinic acid adenine dinucleotide phosphate (NAADP ؉ ) (7), which binds to an unknown receptor. Since its discovery, there is increasing evidence that NAADP ϩ also has a physiological role in Ca 2ϩ signal transduction in vertebrates, including mammalian cells (8). In the vertebrate nervous system, intracellular Ca 2ϩ release by NAADP ϩ has only been demonstrated from rat brain microsome preparations (9) and in frog motoneurons (10). NAADP ϩ -specific binding sites are found in gray and white matter of rat brain, but the cellular specificity of the binding site has not yet been determined (11). The major way of NAADP ϩ synthesis in mammalian tissue takes place under acidic conditions and in the presence of nicotinic acid from NADP ϩ by the type II transmembrane glycoprotein ADP-ribosyl cyclase CD38. In a neutral or alkaline environment, CD38 exclusively catalyzes the conversion of NAD ϩ into cADPR (12). Apart from cell membrane localization, CD38 has been located to various intracellular organelle membranes and can moreover be internalized by endocytosis (13). Therefore, NAADP ϩ synthesis most likely takes place in membranes of intracellular acidic organelles such as lysosomes or late endosomes, whereas CD38 in the plasma membrane synthesizes cADPR. Regarding the mammalian central nervous system, CD38 expression was demonstr...

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