Hypoxic remodeling of Ca2+ stores in type I cortical astrocytes.
Prolonged periods of hypoxia are deleterious to higher brain functions and increase the likelihood of developing dementias. Here, we have used fluorimetric techniques to investigate the effects of chronic hypoxia (2.5% O(2), 24 h) on Ca(2+) stores in type I cortical astrocytes, because such stores are crucial to various astrocyte functions, including Ca(2+)-dependent modulation of neuronal activity. Rises of [Ca(2+)](i) evoked by exposure of astrocytes to bradykinin were enhanced following chronic hypoxia, as were transient increases in [Ca(2+)](i) recorded in Ca(2+)-free perfusate. The enhanced responses were due partly to impaired plasmalemmal Na(+)/Ca(2+) exchange following chronic hypoxia. More importantly, chronic hypoxia increased the Ca(2+) content of mitochondria (as determined by exposing cells to mitochondrial inhibitors), such that they were unable to act as Ca(2+) buffers following bradykinin-evoked Ca(2+) release from the endoplasmic reticulum. Hypoxic enhancement of mitochondrial Ca(2+) content was also observed in confocal images of cells loaded with the mitochondrial Ca(2+) indicator, Rhod-2. Confocal imaging of cells loaded with tetramethylrhodamine ethyl ester, an indicator of mitochondrial membrane potential, indicated that mitochondria were hyperpolarized in astrocytes following chronic hypoxia. Our findings indicate that hypoxia disturbs Ca(2+) signaling in type I astrocytes, primarily by causing mitochondrial Ca(2+) overload.
Smith
Ian F
IF
Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom.
Boyle
John P
JP
Plant
Leigh D
LD
Pearson
Hugh A
HA
Peers
Chris
C
D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D015687:Cell Hypoxia; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002118:Calcium