Single Nucleotide Polymorphism of Human Platelet-activating Factor Receptor Impairs G-protein Activation

Koichi Fukunaga, Satoshi Ishii, Koichiro Asano, Takehiko Yokomizo, Tetsuya Shiomi, Takao Shimizu, Kazuhiro Yamaguchi

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)43025-43030
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number46
DOIs
Publication statusPublished - 2001 Nov 16

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Polymorphism
GTP-Binding Proteins
Platelet Activating Factor
Single Nucleotide Polymorphism
Nucleotides
Chemical activation
WEB 2086
Cricetulus
Ovary
Cells
Mutation
Inositol Phosphates
Chemotaxis
Adenylyl Cyclases
Gene Frequency
Aspartic Acid
Alanine
Genes
platelet activating factor receptor
Calcium

ASJC Scopus subject areas

  • Biochemistry

Cite this

Single Nucleotide Polymorphism of Human Platelet-activating Factor Receptor Impairs G-protein Activation. / Fukunaga, Koichi; Ishii, Satoshi; Asano, Koichiro; Yokomizo, Takehiko; Shiomi, Tetsuya; Shimizu, Takao; Yamaguchi, Kazuhiro.

In: Journal of Biological Chemistry, Vol. 276, No. 46, 16.11.2001, p. 43025-43030.

Research output: Contribution to journalArticle

Fukunaga, Koichi ; Ishii, Satoshi ; Asano, Koichiro ; Yokomizo, Takehiko ; Shiomi, Tetsuya ; Shimizu, Takao ; Yamaguchi, Kazuhiro. / Single Nucleotide Polymorphism of Human Platelet-activating Factor Receptor Impairs G-protein Activation. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 46. pp. 43025-43030.
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