Cyanide-stimulated inositol 1,4,5-trisphosphate formation: an intracellular neurotoxic signaling cascade.
Cyanide-induced neurotoxicity is associated with altered cellular Ca2+ homeostasis resulting in sustained elevation of cytosolic Ca2+. In order to characterize the effect of cyanide on intracellular signaling mechanisms, the interaction of KCN with the inositol 1,4,5-trisphosphate Ca2+ signaling system was determined in the PC12 cell line. KCN in the concentration range of 1.0-100 microM produced a rapid rise in intracellular IP3 levels (peak level occurred within 60 sec); 10 microM KCN elevated intracellular levels of IP3 to 148% of control levels. This response was mediated by phospholipase C (PLC) since U73122, a specific PLC inhibitor, blocked the response. Removal of Ca2+ from the incubation medium and chelation of intracellular Ca2+ with BAPTA partially attenuate the cyanide-stimulated IP3 generation, showing that the response is partially Ca2+ dependent. Also, treatment of cells with nifedipine or LaCl3, Ca2+ channel blockers, partially blocked the generation of IP3. This study shows that cyanide in concentrations as low as 1 microM stimulates IP3 generation that may be mediated by receptor and nonreceptor IP3 production since they have differential dependence on Ca2+. It is proposed that this response is an early intracellular signaling action that can contribute to altered Ca2+ homeostasis characteristic of cyanide neurotoxicity.
Yang
C W
CW
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1334, USA.
Borowitz
J L
JL
Gunasekar
P G
PG
Isom
G E
GE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D011042:Poisons / Q000633:toxicity*; D011190:Potassium Cyanide / Q000633:toxicity*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D011042:Poisons; D004533:Egtazic Acid; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D011190:Potassium Cyanide; D002118:Calcium