Defective polymorphonuclear leukocyte formyl peptide receptor(s) in juvenile periodontitis.

Perez, H D; Kelly, Edward J.; Elfman, Fred; Armitage, Gary C.; Winkler, James R.

doi:10.1172/jci115105

Cited by 77 publications

(49 citation statements)

References 19 publications

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“…2C, first and second lanes, PNGase F digestion of FPR1-transfected HEK 293 cell membranes shifted the FPR1 band from ϳ60 to ϳ35 kDa. This corresponds to the size of the deglycosylated core protein of human neutrophil FPR1 previously reported in the literature (28,32,33). Wild type untransfected HEK 293 cell membranes showed no signal (Fig.…”

Section: Fpr1 Is Expressed By Human Lens Epithelial Cells-fpr1supporting

confidence: 81%

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

Schneider

Weaver

Gaur

et al. 2012

Journal of Biological Chemistry

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Section: Fpr1 Is Expressed By Human Lens Epithelial Cells-fpr1supporting

confidence: 81%

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

Schneider

Weaver

Gaur

et al. 2012

Journal of Biological Chemistry

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“…2, A and B). Altered electrophoretic mobility of the FPR from an LJP patient relative to the FPR from a control subject was observed previously (15). Thus, it is tempting to speculate that the LJP patient studied by Perez et al (15) expressed FPR-C126W.…”

Section: Inefficiency Of Fpr-f110s and Fpr-c126w In Stimulating Gtp␥smentioning

confidence: 73%

“…2). In addition, several fMLP-induced responses in neutrophils from LJP patients such as increases in cytosolic calcium concentration and lysosomal enzyme release are robust (15,16,38). These fMLP responses are incompatible with an almost complete loss and a complete loss of G i protein coupling in FPR-F110S and FPR-C126W, respectively.…”

Section: Inefficiency Of Fpr-f110s and Fpr-c126w In Stimulating Gtp␥smentioning

confidence: 99%

Defective Gi Protein Coupling in Two Formyl Peptide Receptor Mutants Associated with Localized Juvenile Periodontitis

Seifert

Wenzel-Seifert

2001

Journal of Biological Chemistry

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Neutrophils play an important role in host defense against bacterial infections and in the pathogenesis of various inflammatory diseases (1, 2). Neutrophils express GPCRs 1 for the chemoattractants fMLP, complement C5a, interleukin-8, leukotriene B 4 , and platelet-activating factor (3-6). Chemoattractant receptors couple to G i proteins to activate phospholipase C␤2 and phosphoinositide 3-kinase-␥, with subsequent stimulation of chemotaxis, oxygen radical formation, and granule release (3, 7-9). Disruption of the FPR gene in mice increases susceptibility to infection by Listeria monocytogenes (10). However, although at cellular and molecular levels, the human FPR is one of the most extensively studied GPCRs (3-6, 8, 11), the in vivo role of the FPR in man has remained elusive.LJP is a defined periodontal disease that begins at ϳ11-15 years of age, affects the permanent incisors and/or first molars, and is associated with the presence of Actinobacillus actinomycetemcomitans in subgingival pockets. LJP is not associated with other diseases, and there is evidence that LJP is caused by a genetic defect (12, 13). It has been known for a long time that neutrophils from LJP patients show reduced binding of the agonist fMLP and reduced fMLP-induced chemotaxis (14 -16). Genetic analysis of 30 LJP patients revealed that 29 of those patients possess a F110S and/or C126W mutation in the FPR gene (17). In contrast, none of 31 patients with adult periodontitis and none of 20 control subjects possess a F110S or C126W mutation (17). The F110S mutation resides in the third transmembrane domain, whereas the C126W mutation resides in the second intracellular loop (Fig. 1). The second intracellular loop of the FPR is important for G i protein coupling (18), and a C126S mutation uncouples the FPR from G i proteins (19). Based on all these findings, we developed the hypothesis that the underlying cause of LJP is defective G i protein coupling of the FPR. To test this hypothesis, we engineered FLAG epitopetagged FPR-F110S and FPR-C126W and analyzed coupling of these FPR mutants and FPR-WT to the G protein G␣ i2 ␤ 1 ␥ 2 using Sf9 insect cells as the expression system. In previous studies, we already showed that Sf9 insect cells are a very sensitive system for studying G i protein coupling of chemoattractant receptors (20 -22). Here we report that FPR-F110S and FPR-C126W show an almost complete defect and a complete defect in G i protein coupling, respectively. The discrete clinical symptoms associated with the defective FPR indicate that the loss of FPR function in host defense is, for the most part, readily compensated. EXPERIMENTAL PROCEDURESMaterials-The baculovirus encoding G␣ i2 was kindly provided by Dr. A. G. Gilman (Department of Pharmacology, University of Southwestern Medical Center, Dallas, TX). Recombinant baculovirus encoding the unmodified versions of the G protein ␤ 1 ␥ 2 subunits was a kind gift of Dr.

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“…19 Defective PMN formyl peptide receptor(s) offer a plausible explanation for several of the cellular and functional defects reported in AP patients. 11,20,21 At least three fMLP-receptor genes have been localized to chromosome 19, and ligand-binding studies have 23 In vitro studies demonstrate that mutating amino acids from FPR1 ligandbinding domains may influence FPR1 function. 24 The report by Gwinn et al 12 that two SNP mutations in the high-affinity fMLP-receptor, FPR1, were significantly associated with a clinically localized form of AP in African-Americans suggested a possible genetic basis for the disease.…”

Section: Discussionmentioning

confidence: 99%

“…7 Of the PMN anomalies reported in AP, the most frequent finding has been altered fMLP-mediated chemotaxis in African-American patients with the localized form of disease. 8,9 The etiological basis for altered chemotaxis remains unknown, although both innate genetic and acquired anomalies have been proposed. 10,11 Alterations of two codons, one in the second transmembrane domain (c.329T4C/p.F110S) and one in the second intracellular loop (c.378C4G/p.C126W) of the fMLP receptor, have been reported to be significantly associated with a localized form of AP in African American patients.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of human leukocyte N-formylpeptide receptor (FPR1) SNPs in aggressive periodontitis patients

et al. 2003

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Polymorphonuclear neutrophils (PMNs) are attracted to sites of infection by N-formylpeptide (fMLP) chemoattractants. The high-affinity fMLP receptor (FPR1) of phagocytic cells interacts with bacterial fMLP and mediates chemotaxis, degranulation, and superoxide production. These cellular functions are disrupted in PMN from aggressive periodontitis (AP) patients. Two FPR1 gene single nucleotide polymorphisms (SNPs), c.329T4C and c.378C4G, have been associated with a localized form of AP in African-American patients. To evaluate the generality of these SNPs in AP patients, we sequenced a 363 bp interval of the FPR1 gene in an ethnically diverse group of patients (n ¼ 111) and controls (n ¼ 115). Neither c.329T4C nor c.378C4G were detected in the 452 alleles sequenced. Six SNPs were identified including two located in the FPR1 second extracellular loop that were significantly associated with the AP phenotype in African-American patients (p.R190W, P ¼ 0.0033; and p.N192K, P ¼ 0.0018). These two SNPs show three predominant haplotypes, each associated with a different disease risk in African-Americans. These data do not support the hypothesis that the FPR1 SNPs c.329T4C and c.378C4G play an etiologic role in aggressive periodontitis, but do suggest that SNPs in the second extracellular loop may be etiologically important.

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Defective polymorphonuclear leukocyte formyl peptide receptor(s) in juvenile periodontitis.

Abstract: Juvenile periodontitis (JP) is a disease characterized by severe gingival infections. PMN Invest. 1991. 87:971-976.)

Cited by 77 publications

References 19 publications

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

The Leukocyte Chemotactic Receptor FPR1 Is Functionally Expressed on Human Lens Epithelial Cells

Defective Gi Protein Coupling in Two Formyl Peptide Receptor Mutants Associated with Localized Juvenile Periodontitis

Evaluation of human leukocyte N-formylpeptide receptor (FPR1) SNPs in aggressive periodontitis patients

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