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J. Biol. Chem., Vol. 280, Issue 42, 35630-35640, October 21, 2005

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Extracellular Application of Nicotinic Acid Adenine Dinucleotide Phosphate Induces Ca²⁺ Signaling in Astrocytes in Situ^*

From the Max-Delbrück-Center for Molecular Medicine, Cellular Neuroscience, 10 Robert-Rössle-Strasse, Berlin D-13092, Germany

Nicotinic acid adenine dinucleotide phosphate (NAADP⁺) has been identified as a novel second messenger triggering Ca²⁺ release from intracellular stores. Here we report that murine cortical astrocytes in culture and in acute slices respond with transient intracellular Ca²⁺ increases to extracellularly applied NAADP⁺ and express the NAADP⁺ -producing enzyme CD38. The Ca²⁺ transients triggered by NAADP⁺ occurred with an average delay of 35 s as compared with ATP-triggered Ca²⁺ signaling, suggesting that NAADP⁺ may have to enter the cell to act. Blockage of connexin hemichannels (a possible entry route for NAADP⁺ into the cell) reduced the number of astrocytes responding to NAADP⁺. Disruption of lysosomes as the suggested site of NAADP⁺ receptors reduced the number of astrocytes responding to NAADP⁺ strongly. The NAADP⁺ -triggered Ca²⁺ signal also depended on intact endoplasmic reticulum Ca²⁺ stores linked to activation of inositol 1,4,5-trisphosphate receptors and on the activity of voltage-gated Ca²⁺ channels. Adenosine receptor-mediated signaling contributes to the NAADP⁺ -evoked signal, since it is strongly reduced by the adenosine receptor blocker CGS-15943. Moreover, NAADP⁺ triggered responses in all other cell types (cultured cerebellar neurons, microglia, and oligodendrocytes) of the central nervous system.

Received for publication, July 6, 2005 , and in revised form, July 28, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 515 and GRK 238. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Cellular Neuroscience, Max-Delbrück-Center for Molecular Medicine, 10 Robert-Rössle-Strasse, D-13092 Berlin. Tel.: 49-30-9406-3325; Fax: 49-30-9406-3819; E-mail: kettenmann{at}mdc-berlin.de.

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