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J. Biol. Chem., Vol. 277, Issue 23, 20256-20263, June 7, 2002

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Carboxyl-terminal Peptide of -Amyloid Precursor Protein Blocks Inositol 1,4,5-Trisphosphate-sensitive Ca²⁺ Release in Xenopus laevis Oocytes^*

Joung-Hun Kim^§, Jong-Cheol Rah^¶, Scott P. Fraser, Keun-A Chang^¶, Mustafa B. A. Djamgoz, and Yoo-Hun Suh^¶

From the  Neurobiology Group, Department of Biology, Sir Alexander Fleming Bldg., Imperial College of Science, Technology and Medicine, London SW7 2AZ, United Kingdom and the ^¶ Department of Pharmacology, College of Medicine, National Creative Research Initiative Centre for Alzheimer's Dementia, and Neuroscience Research Institute, MRC, Seoul National University, Seoul 110-799, South Korea

The effects of Alzheimer's disease-related amyloidogenic peptides on inositol 1,4,5-trisphosphate receptor-mediated Ca²⁺ mobilization were examined in Xenopus laevis oocytes. Intracellular Ca²⁺ was monitored by electrophysiological measurement of the endogenous Ca²⁺-activated Cl current. Application of a hyperpolarizing pulse released intracellular Ca²⁺ 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 Ca²⁺ release in a dose-dependent manner. Equimolar -amyloid peptides A_1-40 or A_1-42 had no effect, and whereas a truncated carboxyl terminus lacking the A 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 Ca²⁺-dependent Cl channel itself or compromised Ca²⁺ influx. We conclude that the carboxyl terminus of the amyloid precursor protein inhibits inositol 1,4,5-trisphosphate-sensitive Ca²⁺ release and could thus disrupt Ca²⁺ homeostasis and that the carboxyl terminus is much more effective than the -amyloid fragments used. By perturbing the coupling of inositol 1,4,5-trisphosphate and Ca²⁺ release, the carboxyl terminus of the amyloid precursor protein can potentially be involved in inducing the neural toxicity characteristic of Alzheimer's disease.

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