The Chemoattractant Receptor-like Protein C5L2 Binds the C3a des-Arg77/Acylation-stimulating Protein

Kalant, David; Cain, Stuart A.; Maslowska, Magdalena; Sniderman, Allan D.; Cianflone, Katherine; Monk, Peter N.

doi:10.1074/jbc.m206169200

Cited by 169 publications

(169 citation statements)

References 37 publications

(19 reference statements)

Supporting

Mentioning

165

Contrasting

Order By: Relevance

“…7 As previously pointed out by us and others, the action of ASP is a function not only of the prevailing ASP concentration, but also of the sensitivity of the ASP receptor in target tissues to ASP. 1 With the identification of an ASP receptor, C5L2, in adipose tissue and other insulin-sensitive tissues, 70 we can now examine directly the role of ASP in diabetes and test the hypothesis of 'ASP resistance'.…”

Section: Discussionmentioning

confidence: 99%

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

et al. 2005

View full text Add to dashboard Cite

Objective: The purpose of this study was to determine the relationships between adipocyte hormones acylation stimulating protein (ASP), adiponectin, complement C3 (C3) (ASP precursor) and insulin, C-reactive protein (CRP), lipid profiles and insulin resistance in lean vs obese type 2 diabetes subjects. Subjects: Lean type 2 diabetes subjects (DL n ¼ 27) vs obese type 2 diabetes subjects (DO n ¼ 55) were compared to agematched nondiabetic groups (Obese, OB n ¼ 55 and control, CTL n ¼ 50).Results: The DO group demonstrated significant increases in plasma ASP and C3 with decreases in plasma adiponectin as compared to CTL. Interestingly, these increases in ASP and C3 were as high, or greater, in the DL group in spite of normal weight. By contrast adiponectin in the DL group was comparable to CTL, in spite of marked insulin resistance. C3 correlated with insulin, glucose and homeostasis model assessment of insulin resistance (HOMA-IR); ASP correlated with body mass index (BMI), glucose, insulin and plasma lipid parameters (non-esterified fatty acids (NEFA), triglyceride, cholesterol and apolipoprotein B). Adiponectin correlated with BMI, glucose, NEFA, triglyceride, high-density lipoprotein cholesterol and apolipoprotein A1 but not HOMA-IR, ASP or C3. CRP correlated only with HOMA-IR. Conclusion: Increased ASP and C3 are both associated with diabetes and related lipid factors but are not regulated coordinately. Adiponectin appears to be more closely related to body size (decreased in obese subjects) than insulin resistance in these subjects.

show abstract

Section: Discussionmentioning

confidence: 99%

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

et al. 2005

View full text Add to dashboard Cite

show abstract

“…In addition to C5ar, C5l2 represents a second high affinity receptor for C5a and C5a desArg . There is still controversy about the expression of C5l2, its ligands and its functional role in biological responses [4][5][6][7][8]13 . One way in which C5l2 differs from C5ar is in the so-called DRY region of the third intracellular loop (replacement of arginine by leucine), resulting in an uncoupling of C5l2 from G protein interactions 6,7 .…”

Section: Discussionmentioning

confidence: 99%

“…There is still controversy about the expression of C5l2, its ligands and its functional role in biological responses [4][5][6][7][8]13 . One way in which C5l2 differs from C5ar is in the so-called DRY region of the third intracellular loop (replacement of arginine by leucine), resulting in an uncoupling of C5l2 from G protein interactions 6,7 . Binding of C5a (and C5a desArg ) to C5l2 does not result in increased intracellular calcium, although recent evidence suggests that there may be activation of MAPKs in phagocytes and that interaction of C3a desArg with C5l2 might be associated with protein acylation and triglyceride synthesis in adipocytes [6][7][8]13 .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it also remains unclear whether C3a and C3a desarg might exert their anti-inflammatory effects via interaction with C5l2, which has been thought to have anti-inflammatory properties by nonproductively binding C5a [9][10][11][12] . Recent studies suggest that C5l2 can mediate the biological activities of the complement anaphylatoxins C5a and C3a via mitogen-activated protein kinase (MAPK) activation and that C5l2, as a receptor for C3a desArg , contributes to protein acylation and synthesis of triglycerides in adipocytes 7,13 . Like C5ar, C5l2 is abundantly expressed on both myeloid and nonmyeloid cells 14 .…”

mentioning

confidence: 99%

“…There are unresolved disagreements as to whether C3a and C3a desarg bind to C5l2 (refs. 5,7,8 ). Therefore, it also remains unclear whether C3a and C3a desarg might exert their anti-inflammatory effects via interaction with C5l2, which has been thought to have anti-inflammatory properties by nonproductively binding C5a [9][10][11][12] .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Functional roles for C5a receptors in sepsis

Rittirsch

Flierl

Nadeau

et al. 2008

Nat Med

Self Cite

362

425

View full text Add to dashboard Cite

The function of the C5a receptors, C5ar (encoded by C5ar) and C5l2 (encoded by Gpr77), especially of C5l2, which was originally termed a 'default receptor', remains a controversial topic. Here we investigated the role of each receptor in the setting of cecal ligation and puncture-induced sepsis by using antibody-induced blockade of C5a receptors and knockout mice. In 'mid-grade' sepsis (30-40% survival), blockade or absence of either C5ar or C5l2 greatly improved survival and attenuated the buildup of proinflammatory mediators in plasma. In vivo appearance or in vitro release of high mobility group box 1 protein (HMGB1) required C5l2 but not C5ar. In 'high-grade' sepsis (100% lethality), the only protective condition was the combined blockade of C5l2 and C5ar. These data suggest that C5ar and C5l2 contribute synergistically to the harmful consequences in sepsis and that C5l2 is required for the release of HMGB1. Thus, contrary to earlier speculation, C5l2 is a functional receptor rather than merely a default receptor.The complement anaphylatoxin, C5a, is generated during experimental sepsis and has been shown to play adverse roles in survival after cecal ligation and puncture (CLP) 1 16 . In the current work, we describe evidence for the combined roles of C5ar and C5l2 in the harmful outcomes of CLP-induced sepsis, including lethality and the surge of proinflammatory mediators in plasma. These data suggest that both C5ar and C5l2 cooperatively play functional parts in the setting of sepsis and that the role of C5l2 is specifically linked to the release of HMGB1, a known key mediator in CLP-induced lethality. RESULTS Specificity of antibodies to C5a receptorsUsing flow cytometry, we evaluated rabbit polyclonal antibodies to the N-terminal peptide regions of C5ar and C5l2. Antibody to C5ar bound to surfaces of blood neutrophils (PMNs) from wild-type mice (Fig. 1a). When the immunogenic peptide used to raise the antibody to C5ar was added, binding of IgG to PMNs was completely blocked (Fig. 1a). Addition of the C5l2 immunogenic peptide to the C5ar-specific antiserum did not alter the binding of IgG to C5ar (Fig. 1a). Likewise, C5l2-specific antiserum showed binding of IgG to blood PMNs (Fig. 1b). Addition of the immunogenic peptide for C5l2 abolished the IgG binding ( Fig. 1b), whereas addition of irrelevant peptide (immunogenic peptide for C5ar) did not affect binding (Fig. 1b). These data define the specificities of the antibodies to C5ar and C5l2.In order to address the concern that the absence of C5l2 might be associated with reduced expression of C5ar, we assessed the amount of C5ar on PMNs from either wild-type (Gpr77 +/+ ) or Gpr77 -/-mice (Fig. 1c). No quantitative difference in C5ar content was noted on the surface of PMNs from the two groups of mice. Accordingly, when PMNs from C5ar1 -/-and wild-type (C5ar1 +/+ ) mice were stained with the antibody to C5l2, C5ar1 -/-cells had similar expression of C5l2 on their surfaces as compared to cells from wild-type mice (Fig. 1d). These results suggest th...

show abstract

Past and Future Strategies for GPCR Deorphanization

Levoye

Clément

Tenconi

et al. 2010

GPCR Molecular Pharmacology and Drug Targeting

View full text Add to dashboard Cite

The Chemoattractant Receptor-like Protein C5L2 Binds the C3a des-Arg77/Acylation-stimulating Protein

Abstract: The orphan receptor C5L2 has recently been described as a high affinity binding protein for complement fragments C5a and C3a that, unlike the previously described C5a receptor (CD88), couples only weakly to

Cited by 169 publications

References 37 publications

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

Relationships among acylation stimulating protein, adiponectin and complement C3 in lean vs obese type 2 diabetes

Functional roles for C5a receptors in sepsis

Past and Future Strategies for GPCR Deorphanization

Contact Info

Product

Resources

About