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  • FPR family Human FPR was


    FPR family Human FPR was first defined biochemically, in 1976, as a high affinity binding site on the surface of neutrophils for the prototypic N-formyl peptide formyl-methionine-leucyl-phenylalanine (fMLF). It was then cloned in 1990, by Boulay et al. from a differentiated HL-60 myeloid leukemia-cell cDNA library 12., 13.. In transfected cell lines, FPR binds fMLF with high affinity (Kd < 1 nm) and is activated by picomolar to low nanomolar concentrations of fMLF in chemotaxis and calcium ion (Ca2+) mobilization assays. Two additional human genes, designated FPRL1 (FPR-like 1) and FPRL2 (FPR-like 2), were subsequently isolated by low-stringency hybridization using FPR cDNA as a probe 14., 15., 16. and shown to cluster with FPR on human chromosome 19q13.3 15., 16.. FPRL1 is defined as a low-affinity fMLF receptor, based on its activation only by high concentrations of fMLF (μM range) in vitro6., 7.. However, it is unclear whether such concentrations of fMLF could be generated at sites of bacterial infection or tissue injury. Therefore, the role of FPRL1 as another bona fide functional fMLF receptor in vivo remains to be determined. FPRL2 does not bind or respond to N-formyl peptides [17] but instead shares some non-formylated chemotactic peptides identified for FPRL1 18., 19.. Although FPR and FPRL1 were initially detected in phagocytic leukocytes, other cell types also express these receptors (Table 2) but with undefined biological significance. Little information is available about the expression pattern of FPRL2, except that mRNA for this receptor is present in monocytes but not neutrophils [17]. Functional FPRL2 is also expressed in mature dendritic Tariquidar methanesulfonate, hydrate (DCs) [20], which express reduced levels of FPR but do not appear to express FPRL1 21., 22.. The FPR gene family has a complex evolutionary history. The number of genes in the family varies considerably in different mammalian species, indicating differential gene expansion or extinction and suggesting the presence of differential selective pressures. In particular, the murine FPR gene family has at least six members in contrast to only three in humans (Table 2) [23]. Fpr1 encodes mFPR1 (murine FPR1), which is considered the murine orthologue of human FPR, whereas both Fpr-rs2 and Fpr-rs1 encode receptors that are structurally and functionally most similar to human FPRL1 [24]. mFPR2, encoded by Fpr-rs2, is an fMLF receptor, whereas the product of murine Fpr-rs1, functions as a receptor for the lipid mediator lipoxin A4 (LXA4) [25]; FPRL1 can function as both an fMLF and a LXA4 receptor 6., 7., 8.. The other four murine formyl-peptide receptor gene family members are expressed in leukocytes but encode putative receptors because ligands have not been identified (Table 2). The complex evolution of the FPR gene family is also apparent from the high sequence divergence between species orthologues (∼30% between human and mouse), which is a characteristic common to immunoregulatory proteins. Moreover, in a single species closely related members of the gene family might respond to distinct selective pressures. Thus, in humans, the FPR open-reading frame is highly polymorphic, whereas a parallel analysis of FPRL1 has revealed no polymorphism [26].
    FPR signal transduction On agonist binding, heterotrimeric Gi proteins coupled to FPR rapidly dissociate into α and βγ subunits, activating signaling molecules and pathways shared with most other leukocyte chemoattractant receptors, including FPRL1 and FPRL2 11., 12., 13., 18., 19. (Fig. 1). CD38, a transmembrane glycoprotein, which catalyzes the production of cyclic ADP-ribose (cADPR) from its substrate NAD+, seems to be an exception because it appears to be an essential and specific transducer of fMLF signals in mouse neutrophils (Fig. 1). Neutrophils from CD38−/− mice fail to migrate in response to fMLF in vitro and fail to accumulate at sites of Streptococcus pneumoniae infection in vivo[27]. cADPR directly induces intracellular Ca2+ release in neutrophils by acting at ryanodine receptors, and is required for a sustained extracellular Ca2+ influx in neutrophils stimulated by fMLF. Nevertheless, it is not clear whether CD38 controls the function of mFPR1 or mFPR2 or both.