Amyloid beta peptide enhanced bradykinin-mediated inositol (1,4,5)trisphosphate formation and cytosolic free calcium.
Deposition of amyloid beta protein (A beta) and alteration in signal transduction systems may have pathophysiological significance in Alzheimer's disease (AD). This study tested the hypothesis that bradykinin (BK) receptor-mediated signal transduction systems in PC12 cells are altered after treatment with A beta at a concentration not toxic to cells. Exposure to varying doses of A beta 25-35 (1-10 microM) for 18 hrs significantly reduced the number of viable cells, while lower concentrations (0.01-0.1 microM) and control peptide in scramble sequence had no effect. In addition, prolonged exposure of PC12 cells to a sublethal dose of A beta 25-35 (0.1 microM) affected the receptor-mediated signal transduction pathways. BK induced both accumulation of Ins(1,4,5)P3 and elevation in cytosolic free calcium concentration ([Ca2+]i) in the control cells. These responses were further enhanced in the cells treated with A beta. Under similar conditions, A beta-treated cells also demonstrated alterations in the number and affinity of BK receptors. Alternatively, extracellular addition of A beta elevated [Ca2+]i rapidly, without detectable alterations in Ins(1,4,5)P3. This rapid elevation was dependent on extracellular calcium, suggesting that A beta induced calcium influx. Taken together, the results demonstrated that treatment with a sublethal dose of A beta peptide for 18 hrs enhanced BK receptor mediated Ins(1,4,5)P3 formation and mobilization of intracellular calcium, associated with a modification in BK receptors. Changes in the balance of these receptor-mediated signals prior to cell injury could be an important underlying mechanism for A beta peptide-induced degenerative alteration in AD.
Huang
H M
HM
Department of Education and Medical Research, Taichung Veterans General Hospital, Taiwan, ROC. hmhuang@vghtc.vghtc.gov.tw
Ou
H C
HC
Hsueh
S J
SJ
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001920:Bradykinin / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D009420:Nervous System / Q000187:drug effects; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D018002:Receptors, Bradykinin / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D014316:Tritium
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D018002:Receptors, Bradykinin; C074636:amyloid beta-protein (25-35); D014316:Tritium; D015544:Inositol 1,4,5-Trisphosphate; D001920:Bradykinin; D002118:Calcium