Protease nexin-1 and thrombin modulate neuronal Ca2+ homeostasis and sensitivity to glucose deprivation-induced injury.
Protease nexin-I (PN-1) is a 44 kDa serine proteinase inhibitor that rapidly inhibits thrombin by forming SDS stable complexes with serine at the catalytic site of the protease. Levels of both PN-1 and thrombin are increased in the brain in response to insults such as ischemia, suggesting roles in neural injury and repair processes. We now report that PN-1-protected cultured rat hippocampal neurons against glucose deprivation- induced damage (GDID), and the protection was abolished by equimolar thrombin. PN-1 reduced resting intracellular free calcium levels ([Ca2+]i) and attenuated the elevation of [Ca2+]i normally associated with GDID. Thrombin reduced neuronal survival and caused a significant increase in [Ca2+]i. Submaximally toxic levels of thrombin exacerbated GDID. Calcium responses to thrombin were attenuated in neurons contacting PN-1 immunoreactive astrocytes. These findings suggest that PN-1 and thrombin play important roles in modulating neuronal calcium responses, and vulnerability, to metabolic/excitotoxic insults.
Smith-Swintosky
V L
VL
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Zimmer
S
S
Fenton
J W
JW
Mattson
M P
MP
D016564:Amyloid beta-Protein Precursor; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology*; D004347:Drug Interactions; D005947:Glucose / Q000172:deficiency*; D006706:Homeostasis / Q000187:drug effects; D007425:Intracellular Membranes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000494:pharmacology; D009994:Osmolar Concentration; D058255:Protease Nexins; D051381:Rats; D011956:Receptors, Cell Surface; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D009498:Neurotoxins; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D013917:Thrombin; D005947:Glucose; D002118:Calcium