Carboxyl-terminal peptide of beta-amyloid precursor protein blocks inositol 1,4,5-trisphosphate-sensitive Ca2+ release in Xenopus laevis oocytes.
The effects of Alzheimer's disease-related amyloidogenic peptides on inositol 1,4,5-trisphosphate receptor-mediated Ca(2+) mobilization were examined in Xenopus laevis oocytes. Intracellular Ca(2+) was monitored by electrophysiological measurement of the endogenous Ca(2+)-activated Cl(-) current. Application of a hyperpolarizing pulse released intracellular Ca(2+) in oocytes primed by pre-injection of a non-metabolizable inositol 1,4,5-trisphosphate analogue. The carboxyl terminus of the amyloid precursor protein inhibited inositol 1,4,5-trisphosphate receptor-mediated intracellular Ca(2+) release in a dose-dependent manner. Equimolar beta-amyloid peptides Abeta(1-40) or Abeta(1-42) had no effect, and whereas a truncated carboxyl terminus lacking the Abeta domain was equipotent to the full-length one, a carboxyl terminus fragment lacking the NPTY sequence was less effective than the full-length fragment. The inhibition induced by the carboxyl terminus was not associated with the block of the Ca(2+)-dependent Cl(-) channel itself or compromised Ca(2+) influx. We conclude that the carboxyl terminus of the amyloid precursor protein inhibits inositol 1,4,5-trisphosphate-sensitive Ca(2+) release and could thus disrupt Ca(2+) homeostasis and that the carboxyl terminus is much more effective than the beta-amyloid fragments used. By perturbing the coupling of inositol 1,4,5-trisphosphate and Ca(2+) release, the carboxyl terminus of the amyloid precursor protein can potentially be involved in inducing the neural toxicity characteristic of Alzheimer's disease.
Kim
Joung-Hun
JH
Neurobiology Group, Department of Biology, Sir Alexander Fleming Bldg., Imperial College of Science, Technology and Medicine, London SW7 2AZ, United Kingdom.
Rah
Jong-Cheol
JC
Fraser
Scott P
SP
Chang
Keun-A
KA
Djamgoz
Mustafa B A
MB
Suh
Yoo-Hun
YH
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium