Hypoxic enhancement of quantal catecholamine secretion. Evidence for the involvement of amyloid beta-peptides.
Prolonged exposure to hypoxia (10% O(2)) enhanced quantal catecholamine release evoked from O(2)-sensing pheochromocytoma (PC12) cells, as monitored using single-cell amperometric recordings. The enhancement of exocytosis was apparent after 12 h of hypoxia and was maximal at 24 h. Elevated levels of secretion were due to the emergence of a Ca(2+) influx pathway that persisted during complete blockade of known voltage-gated Ca(2+) channels. Secretion triggered by this Ca(2+) influx was severely reduced by known inhibitors of Alzheimer's amyloid beta-peptides (AbetaPs), including an N terminus-directed monoclonal antibody. The enhancing effect on secretion of chronic hypoxia was mimicked closely by direct application of AbetaP to cells under normoxic conditions, although the effects of AbetaP were more rapid at onset, being maximal after only 6 h. The present results suggest that prolonged hypoxia can induce formation of Ca(2+)-permeable AbetaP channels and that such induction can lead directly to excessive neurosecretion. This is a potential contributory factor to AbetaP pathophysiology following cerebral ischemia.
Taylor
S C
SC
Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom.
Batten
T F
TF
Peers
C
C
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism*; D015687:Cell Hypoxia; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications; D010100:Oxygen / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D051381:Rats
D016229:Amyloid beta-Peptides; D002395:Catecholamines; D010446:Peptide Fragments; D002104:Cadmium; D011188:Potassium; D010100:Oxygen; D002118:Calcium