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 Ca(2+) signalling in non-excitable cells is poorly understood, yet crucial to our understanding of Ca(2+)-dependent cell functions in physiological and pathological situations. Here, we demonstrate that hypoxia mobilizes Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.
Aley
Parvinder K
PK
School of Medicine, Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, UK.
Murray
Hilary J
HJ
Boyle
John P
JP
Pearson
Hugh A
HA
Peers
Chris
C
D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D010100:Oxygen / Q000502:physiology; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
C493642:8-bromo-cyclic-ADP-ribose; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D009536:Niacinamide; D010738:Type C Phospholipases; D036541:ADP-ribosyl Cyclase; D010100:Oxygen; D001920:Bradykinin; D002118:Calcium