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The Journal of Neuroscience, November 12, 2003, 23(32):10302-10310

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Cellular/Molecular
A Calcium-Induced Calcium Influx Factor, Nitric Oxide, Modulates the Refilling of Calcium Stores in Astrocytes

Nianzhen Li,¹ Jai-Yoon Sul,² and Philip G. Haydon²

¹Department of Zoology and Genetics, Iowa State University, Ames, Iowa 50011, and ²Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

The roles of nitric oxide are primarily undefined in astrocytes, cells that are active partners in synaptic transmission. Because nitric oxide synthases are present in astrocytes, we imaged the formation of nitric oxide in cultured murine cortical astrocytes using DAF-FM (4-amino-5-methylamino-2',7'-difluorofluorescein diacetate). We demonstrated that physiological concentrations of ATP induced a Ca²⁺-dependent production of nitric oxide. We then investigated the roles of nitric oxide in astrocytic Ca²⁺ signaling by exogenous application of a nitric oxide donor and found that nitric oxide induced an influx of external Ca²⁺. Because these observations raise the possibility that nitric oxide-dependent Ca²⁺ influx could lead to the refilling of internal stores with Ca²⁺, we directly monitored the Ca²⁺ levels of the cytosol and of internal stores while manipulating nitric oxide. Cultures were coloaded with mag-fluo-4 and X-rhod-1 to differentially load the internal stores and cytosol, respectively. ATP induced a cytosolic increase in Ca²⁺ that results from the IP₃-dependent release of Ca²⁺ from internal stores, detected as a simultaneous reduction in mag-fluo-4 and an increase in X-rhod-1 fluorescence. To monitor store refilling, we measured the recovery of mag-fluo-4 fluorescence after removal of ATP. When nitric oxide signaling was blocked by the nitric oxide scavenger 2-phenyl-4,4,5,5-ketramethyl-imidazoline-1-oxyl-3-oxide or by the nitric oxide synthase inhibitor N^G-monomethyl-L-arginine, fluorescence recovery was significantly reduced. These data suggest that transmitters that induce Ca²⁺ signaling in astrocytes lead to the Ca²⁺-dependent synthesis of nitric oxide. This in turn stimulates a Ca²⁺ influx pathway that is, in part, responsible for the refilling of internal Ca²⁺ stores.

Key words: nitric oxide; astrocyte; calcium influx; internal calcium stores; DAF-FM; mag-fluo-4; ATP; tripartite synapse

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Received July 29, 2003; revised September 23, 2003; accepted September 24, 2003.

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