Targeted Disruption of the Leukotriene B4Receptor in Mice Reveals Its Role in Inflammation and Platelet-Activating Factor–Induced Anaphylaxis

Haribabu, Bodduluri; Verghese, Margrith W.; Steeber, Douglas A.; Sellars, Dwight D.; Bock, Cheryl B.; Snyderman, Ralph

doi:10.1084/jem.192.3.433

Cited by 160 publications

(150 citation statements)

References 25 publications

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“…Studies using mice with a disrupted BLT1 gene confirm that BLT1 functions in acute inflammation and immediate hypersensitivity as well as in leukocyte activations (45,46). The BLT1-signaling pathway involves activation of phosphoinositide-specific phospholipase C␤ via Bordetella pertussis toxin (PTX)-sensitive (G i/o ) and PTX-resistant (G 16 , G 14 ) G-proteins (29,47).…”

Section: Discussionmentioning

confidence: 99%

Helix 8 of the Leukotriene B4 Receptor Is Required for the Conformational Change to the Low Affinity State after G-protein Activation

Okuno

Ago

Terawaki

et al. 2003

Journal of Biological Chemistry

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Recent studies have revealed that G-protein-coupled receptors contain a putative cytoplasmic helical domain, helix 8. Leukotriene B 4 (LTB 4 ) receptor 1 derivatives with truncated or mutated helix 8 showed much higher LTB 4 binding than wild-type (WT) receptors. Similar to the WT receptor, LTB 4 promoted guanosine 5-3-O-(thio)triphosphate (GTP␥S) binding in these mutants. Unlike the WT receptor, however, the addition of GTP␥S did not inhibit LTB 4 binding to the mutant receptors. Scatchard analyses revealed that mutants maintained high affinity for LTB 4 , even in the presence of excess GTP␥S. Consistently, mutant receptors showed a more prolonged Ca 2؉ mobilization and cellular metabolic activation than the WT receptor. From mutational studies and three-dimensional modeling based on the structure of bovine rhodopsin, we conclude that the helix 8 of LTB 4 receptor 1 plays an important role in the conformational change of the receptor to the low affinity state after G-protein activation, possibly by sensing the status of coupling G␣ subunits as GTP-bound.The activation of different classes of plasma membrane receptors regulates various biological functions in cells. The majority of these receptors belong to a superfamily of G-proteincoupled receptors (GPCRs), 1 whose genes occupy more than 1% of the mammalian genes (1, 2). In general, ligand binding to GPCR results in a conformational change of the receptor that stimulates the activation of heterotrimeric G-proteins. All GPCRs are believed to share a common three-dimensional structure consisting of seven ␣-helical transmembrane (TM) domains connected by three intracellular (i 1 , i 2 , and i 3 ) and extracellular (e 1 , e 2 , and e 3 ) loops with intracellular C-terminal and extracellular N-terminal tails. The extracellular and transmembrane regions of the receptor are involved in ligand binding, whereas the intracellular surface is important for the activation of heterotrimeric G-proteins (3).Recent studies reveal that the cytoplasmic tails of GPCRs have important roles, such as receptor trafficking, desensitization, dimerization, and intracellular signaling (4, 5). In the case of GABA B (␥-aminobutyric acid type B) receptors, only heterodimers consisting of GABA B 1 and GABA B 2 subunits are functional (6 -8). Surface expression of the assembled complexes is regulated through a dimerization-dependent trafficking checkpoint (9, 10). Studies have also shown that segments of the proximal C-terminal tail after the seventh transmembrane domain (TM7) in GPCRs are crucial for receptor transport to the cell surface. Naturally occurring truncations before TM7 of rhodopsin and vasopressin (V2) receptor result in endoplasmic reticulum-arrested receptor transport, leading to the inherited diseases retinitis pigmentosa and nephrogenic diabetes insipidus, respectively (11). Truncations within the proximal C terminus of V2 and luteinizing hormone/choriogonadotropin receptors also impair their transport, whereas deletions of more distal portions have no effect (12, 13). Also,...

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Section: Discussionmentioning

confidence: 99%

Helix 8 of the Leukotriene B4 Receptor Is Required for the Conformational Change to the Low Affinity State after G-protein Activation

Okuno

Ago

Terawaki

et al. 2003

Journal of Biological Chemistry

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“…In animal models for arthritis, skin inflammation, and peritonitis, LTB 4 antagonists reduce clinical symptoms (18 -20). Moreover, in mice deficient for the LTB 4 receptor BLT1, the inflammatory response in a peritonitis model is significantly reduced, suggesting an important role for LTB 4 in PMN chemotaxis in vivo (21).…”

Section: P Olymorphonuclear Neutrophils (Pmn)mentioning

confidence: 99%

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Kavelaars

Vroon

Raatgever

et al. 2003

The Journal of Immunology

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Directed migration of polymorphonuclear neutrophils (PMN) is required for adequate host defense against invading organisms and leukotriene B4 (LTB4) is one of the most potent PMN chemoattractants. LTB4 exerts its action via binding to BLT1, a G protein-coupled receptor. G protein-coupled receptors are phosphorylated by G protein-coupled receptor kinases (GRK) in an agonist-dependent manner, resulting in receptor desensitization. Recently, it has been shown that the human BLT1 is a substrate for GRK6. To investigate the physiological importance of GRK6 for inflammation and LTB4 signaling in PMN, we used GRK6-deficient mice. The acute inflammatory response (ear swelling and influx of PMN into the ear) after topical application of arachidonic acid was significantly increased in GRK6−/− mice. In vitro, GRK6−/− PMN showed increased chemokinetic and chemotactic responses to LTB4. GRK6−/− PMN respond to LTB4 with a prolonged increase in intracellular calcium and prolonged actin polymerization, suggesting impaired LTB4 receptor desensitization in the absence of GRK6. However, pre-exposure to LTB4 renders both GRK6−/− as well as wild-type PMN refractory to restimulation with LTB4, indicating that the presence of GRK6 is not required for this process to occur. In conclusion, GRK6 deficiency leads to prolonged BLT1 signaling and increased neutrophil migration.

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“…Recently, a second human receptor for LTB 4 (BLT2) was cloned and shown to have lower affinity for LTB 4 and wider tissue distribution (8,9). The recent development of mice with disrupted BLT1 suggests a major role for BLT1 in acute inflammation and immediate hypersensitivity as well as in leukocyte functions such as chemotaxis and firm adhesion to endothelium in response to LTB 4 (10,11). Devchand and collaborators (12) have also shown that LTB 4 can bind to the peroxisome proliferator-activated receptor ␣ with low affinity and may have a role in activating genes that terminate inflammatory processes.…”

Section: Leukotriene B 4 (Ltb 4 )mentioning

confidence: 99%

Threonine 308 within a Putative Casein Kinase 2 Site of the Cytoplasmic Tail of Leukotriene B4 Receptor (BLT1) Is Crucial for Ligand-induced, G-protein-coupled Receptor-specific Kinase 6-mediated Desensitization

Gaudreau

Gouill

Venne

et al. 2002

Journal of Biological Chemistry

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Targeted Disruption of the Leukotriene B4Receptor in Mice Reveals Its Role in Inflammation and Platelet-Activating Factor–Induced Anaphylaxis

Cited by 160 publications

References 25 publications

Helix 8 of the Leukotriene B4 Receptor Is Required for the Conformational Change to the Low Affinity State after G-protein Activation

Helix 8 of the Leukotriene B4 Receptor Is Required for the Conformational Change to the Low Affinity State after G-protein Activation

Increased Acute Inflammation, Leukotriene B4-Induced Chemotaxis, and Signaling in Mice Deficient for G Protein-Coupled Receptor Kinase 6

Threonine 308 within a Putative Casein Kinase 2 Site of the Cytoplasmic Tail of Leukotriene B4 Receptor (BLT1) Is Crucial for Ligand-induced, G-protein-coupled Receptor-specific Kinase 6-mediated Desensitization

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