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J. Biol. Chem., Vol. 276, Issue 46, 43025-43030, November 16, 2001
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From the Various proinflammatory and vasoactive actions of
platelet-activating factor (PAF) are mediated through a specific
G-protein-coupled PAF receptor (PAFR). We identified a novel DNA
variant in the human PAFR gene, which substitutes an aspartic acid for
an alanine residue at position 224 (A224D) in the putative third
cytoplasmic loop. This mutation was observed in a Japanese
population at an allele frequency of 7.8%. To delineate the functional
consequences of this structural alteration, Chinese hamster ovary cells
were stably transfected with constructs encoding either wild-type or A224D mutated PAFR. No significant difference was observed in the
expression level of the receptor or the affinity to PAF or to an
antagonist, WEB2086, between the cells transfected with wild-type and
mutant PAFR. Chinese hamster ovary cells expressing A224D mutant PAFR
displayed partial but significant reduction of PAF-induced
intracellular signals such as calcium mobilization, inositol phosphate
production, inhibition of adenylyl cyclase, and chemotaxis. These
findings suggest that this variant receptor produced by a naturally
occurring mutation exhibits impaired coupling to G-proteins and may be
a basis for interindividual variation in PAF-related physiological
responses, disease predisposition or phenotypes, and drug responsiveness.
Single Nucleotide Polymorphism of Human Platelet-activating
Factor Receptor Impairs G-protein Activation*
,
,,
Department of Medicine, Keio University
School of Medicine, Tokyo 160-8582, Japan, the § Department
of Biochemistry and Molecular Biology, Faculty of Medicine, the
University of Tokyo, Tokyo 113-0033, Japan, and ¶ CREST of Japan
Science and Technology Corporation, Tokyo 113-0033, Japan
*
This work was supported in part by grants-in-aid from the
Ministry of Education, Culture, Sports, Science, and Technology and the
Ministry of Health Labor and Welfare of Japan and by a grant from the
Yamanouchi Foundation for Metabolic Disorders.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Cardiopulmonary
Division, Dept. of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Tel.: 81-3-3353-1211; Fax: 81-3-3353-2502; E-mail: ko-asano@qa2.so-net.ne.jp.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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