Structural Determinants Regulating Expression of the High Affinity Leukotriene B4 Receptor

Mutational analysis of determinants located in the C-terminal (C) tail of the high affinity leukotriene (LT) B4 receptor, BLT1, was performed to assess their significance in BLT1 trafficking. When expressed in COS-7 cells, a BLT1 deletion mutant lacking the C-tail (G291stop) displayed higher numbers of binding sites and increased signal transduction compared with wild-type (WT) BLT1. Addition of the C-tail from either the platelet-activating factor receptor or the LTD4 receptor, CysLT1, did not restore WT phenotype. Moreover, the number of LTB4 binding sites was higher in the chimeras than in the WT BLT1, suggesting the requirement for specific structural determinants within the BLT1 C-tail. Elimination of a distal C-tail dileucine motif (Leu304-Leu305), but not the proximal (Leu292-Leu293) motif, altered BLT1 pharmacological characteristics and caused a moderate constitutive receptor activation. Surprisingly, all mutant receptors were efficiently delivered to the plasma membrane, but not to a greater extent than WT BLT1, as assessed by flow cytometry. Furthermore, substitution of Leu304-Leu305 prevented LTB4-induced BLT1 internalization. Molecular modeling of BLT1 on the bovine rhodopsin receptor scaffold strongly suggested the involvement of the distal dileucine motif (Leu304-Leu305) in a hydrophobic core, including intrahelical interactions within α-helix VIII and interhelical interactions with residues of helix I. Disruption of this hydrophobic core is proposed to increase the population of receptors in the active form, to restrain their trafficking and to facilitate the activation of BLT1 as indicated by the increased maximal level of binding of the ligand and constitutive activation of the receptor. Mutational analysis of determinants located in the C-terminal (C) tail of the high affinity leukotriene (LT) B4 receptor, BLT1, was performed to assess their significance in BLT1 trafficking. When expressed in COS-7 cells, a BLT1 deletion mutant lacking the C-tail (G291stop) displayed higher numbers of binding sites and increased signal transduction compared with wild-type (WT) BLT1. Addition of the C-tail from either the platelet-activating factor receptor or the LTD4 receptor, CysLT1, did not restore WT phenotype. Moreover, the number of LTB4 binding sites was higher in the chimeras than in the WT BLT1, suggesting the requirement for specific structural determinants within the BLT1 C-tail. Elimination of a distal C-tail dileucine motif (Leu304-Leu305), but not the proximal (Leu292-Leu293) motif, altered BLT1 pharmacological characteristics and caused a moderate constitutive receptor activation. Surprisingly, all mutant receptors were efficiently delivered to the plasma membrane, but not to a greater extent than WT BLT1, as assessed by flow cytometry. Furthermore, substitution of Leu304-Leu305 prevented LTB4-induced BLT1 internalization. Molecular modeling of BLT1 on the bovine rhodopsin receptor scaffold strongly suggested the involvement of the distal dileucine motif (Leu304-Leu305) in a hydrophobic core, including intrahelical interactions within α-helix VIII and interhelical interactions with residues of helix I. Disruption of this hydrophobic core is proposed to increase the population of receptors in the active form, to restrain their trafficking and to facilitate the activation of BLT1 as indicated by the increased maximal level of binding of the ligand and constitutive activation of the receptor. A variety of stimuli, including light, neurotransmitters, hormones, and inflammatory lipid mediators produce their effects via activation of G-protein-coupled receptors (GPCRs). 1The abbreviations used are: GPCRs, G-protein-coupled receptors; BLT1, leukotriene B4 receptor; CMV, cytomegalovirus; G-protein, GTP-binding regulatory protein; GRK, GPCR kinase; HEK, human embryonic kidney; IP, inositol phosphate(s); LTB4, leukotriene B4; PI, phosphoinositide; TM, transmembrane; WT, wild type; FITC, fluorescein isothiocyanate; PAFR, platelet-activated factor receptor. Taking into account the heterogeneity of ligands, it is interesting that all members of this superfamily of receptors share the same topology characterized by the presence of seven transmembrane α-helices. Conserved residues within subfamily A (related to rhodopsin) are localized throughout these helices, serving as reference points for sequence alignments. Biophysical and biochemical evidence indicate that upon photoactivation, relative movements of transmembrane (TM) 3 and TM6 occur in rhodopsin; similarly, rearrangement of the cytoplasmic proximal portion of TM7 relative to TM1 and of TM2 relative to the intracellular helix VIII were also observed (reviewed in Ref. 1Gether U. Asmar F. Meinild A.K. Rasmussen S.G. Pharmacol. Toxicol. 2002; 91: 304-312Crossref PubMed Scopus (76) Google Scholar). Through structural mimicry, despite the incredible diversity of ligands, GPCRs presumably share the core function of activation through similar conformational changes (2Ballesteros J. Shi L. Javitch J.A. Mol. Pharmacol. 2001; 60: 1-19Crossref PubMed Scopus (405) Google Scholar). GPCRs exist in equilibrium between the inactive (R) and active (R*) conformations, as described in the cubic ternary model of GPCR activation (3Weiss J.M. Morgan P.H. Lutz M.W. Kenakin T.P. J. Theor. Biol. 1996; 178: 169-172Crossref Scopus (97) Google Scholar). Stabilizing networks of intramolecular interactions constrain the receptor in an inactive conformation. Disruption of these stabilizing interactions leads to isomerization of the population of receptors into the active conformation (R*). Several mutations have been described to facilitate the isomerization of receptors from the R to the R* state, leading to higher basal receptor activity in the absence of agonist (1Gether U. Asmar F. Meinild A.K. Rasmussen S.G. Pharmacol. Toxicol. 2002; 91: 304-312Crossref PubMed Scopus (76) Google Scholar, 4Cai K. Klein-Seetharaman J. Farrens D. Zhang C. Altenbach C. Hubbell W.L. Khorana H.G. Biochemistry. 1999; 38: 7925-7930Crossref PubMed Scopus (82) Google Scholar, 5Claeysen S. Sebben M. Becamel C. Bockaert J. Dumuis A. Mol. Pharmacol. 1999; 55: 910-920PubMed Google Scholar, 6Parnot C. Bardin S. Miserey-Lenkei S. Guedin D. Corvol P. Clauser E. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7615-7620Crossref PubMed Scopus (69) Google Scholar). 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Trejo J. J. Biol. Chem. 2002; 277: 1292-1300Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). 2Z. Chen, R. Gaudreau, C. Le Gouill, M. Rola-Pleszczynski, and J. Stankova, manuscript in preparation. The adaptin protein (AP) complexes participate in the formation of clathrin-coated pits (CCP) and sorting of GPCRs to CCP J.A. Caron M.G. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). also specific sorting signal in cytoplasmic of transmembrane as the and and is a with a hydrophobic and sorting T. Annu. Rev. Cell Dev. Biol. 1999; 15: 705-732Crossref PubMed Scopus (425) Google Scholar, R. M. P. 1999; PubMed Scopus Google Scholar, A. Biochemistry. 2001; PubMed Scopus Google Scholar). The latter have been in of CCP trafficking of transmembrane including GPCRs R. M. P. 1999; PubMed Scopus Google Scholar, A. Biochemistry. 2001; PubMed Scopus Google Scholar, F. 1992; Full Text PDF PubMed Scopus Google Scholar, S. J. Cell Biol. 1995; PubMed Scopus Google Scholar, K. I. J. Cell Biol. PubMed Scopus Google Scholar, L. J. Cell Sci. 2000; PubMed Google Scholar, E. L. L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. L. M.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M.J. J.L. Benovic J.L. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, K. I. M. A. M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). have the C-terminal (C) tail of GPCRs as a for of the GPCR including receptor activation and The of rhodopsin in inactive the presence of an located in the C-tail distal to helix K. T. T. Le I. T. M. M. 2000; PubMed Scopus Google Scholar). as phosphorylation and in the C-tail are in receptor D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google and activation M. A. S. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). are as sites for J. P. Dumuis A. L. PubMed Scopus Google Scholar). the specific determinants located in the C-tail were in the activation and trafficking of the high affinity human leukotriene receptor LTB4 is a inflammatory from of as as (reviewed in Ref. M. Full Text PDF Scopus Google J. M. 1992; Google Scholar, J. M. Biochem. J. 1992; PubMed Scopus Google Scholar, M. J. 1992; PubMed Google Scholar). LTB4 through with specific plasma receptors affinity for the a high affinity LTB4 receptor, BLT1 T. T. K. T. PubMed Scopus Google and affinity receptor, T. K. K. T. T. J. 2000; PubMed Scopus Google share Several structural determinants in the of transmembrane protein trafficking are in the BLT1 C-tail and are as as in the human that within the BLT1 C-tail structural in as as in arrestin-independent and and BLT1 regulatory an R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google that a BLT1 deletion mutant (G291stop) lacking the expressed in COS-7 cells, higher numbers of LTB4 binding sites and increased signal transduction compared with the WT receptor R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). that specific structural determinants of BLT1 C-tail the are this receptor are located of the intracellular phosphorylation sites as as dileucine to structural determinants of BLT1 was a from M. I. was a from Benovic and their were as and all from bovine and from bovine from and from to and from LTB4 from from fluorescein from from of (WT) and The of WT BLT1 was described R. Le C. S. S. J. M. Biochem. J. 1998; PubMed Scopus Google Scholar). to of of BLT1, the was by the sequence in WT and mutant BLT1. The mutant was also described R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The mutant receptors were by were to BLT1 core receptor the with the C-terminal tail of either from or from The and are to or and mutant BLT1 were also by mutant BLT1 is by the of the by the number and the of the were into and receptor were of to or of the receptor. The human and were in the of a and in Cell and and were in with with bovine and were with and were performed were for with the COS-7 were with of WT or mutant BLT1. were and in and in bovine T. E. K. T. J. Biol. Chem. Full Text PDF PubMed Google in were also for the binding were on with and of LTB4, for binding were to binding was in presence of LTB4 and than of was from by and a with of in the was in a were in and with WT or mutant BLT1 in with of were and the with were and was as described R. Le C. S. S. J. M. Biochem. J. 1998; PubMed Scopus Google Scholar). in to the basal activity was by the between the basal of mutant and WT the WT or mutant BLT1 were to flow were as described R. Le C. S. S. J. M. Biochem. J. 1998; PubMed Scopus Google with by with fluorescein were performed on a flow in were with of WT or mutant BLT1 with of or the as indicated in for were to with and for with LTB4 or was and the were for were on and were with analysis was as described that was performed were to the were and of receptor internalization was on either the of or on the of cells, with compared with with the Molecular modeling and of BLT1 were the of the were performed on an as described M. L. A. J. S. R. P. E. J. Pharmacol. 2002; PubMed Scopus Google Scholar). a sequence between the of BLT1 and the bovine rhodopsin was performed the The of the were as to the of the the in rhodopsin and human BLT1 and is the in the and The of the were to the sequence of the BLT1. from of the the model was to the with a P. J. M. PubMed Scopus Google Scholar). this the and the of residues were their in the rhodopsin A of was used with for were and the were to were for significance were WT and mutant BLT1 were expressed in a in to and structural in BLT1 trafficking and receptor activation. located in the C-terminal tail of the receptor were with to receptor to the and of BLT1 C-tail for Regulation of BLT1 reported that a BLT1 (G291stop) increased numbers of binding sites and a greater in to LTB4 than WT BLT1 R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). to BLT1 determinants receptors of the core of residues the of TM7 of BLT1 and the C-tail of either the or the LTD4 receptor The in the C-tail of receptor are in receptors and were expressed in COS-7 and were the plasma as assessed by binding analysis of binding the presence of of binding sites high affinity for LTB4 were higher than the for WT BLT1 characteristics of WT and in a receptors were to LTB4 was in COS-7 protein and either or WT receptor. Surprisingly, in to of LTB4, was increased for and in with WT as Furthermore, the increased of the BLT1 to LTB4 was with a higher number of binding as by binding that the C-tail of WT BLT1 a signal that is not in or BLT1 trafficking or the to the structural determinants in the C-tail that BLT1 a BLT1 mutant binding characteristics similar to WT BLT1 R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google the cytoplasmic residues of structural determinants located within the C-tail in receptor sites and dileucine the of and sites did not the increase in binding numbers observed with the BLT1. Moreover, phosphorylation sites within this been on binding R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and not BLT1 C-tail dileucine were of as and are in trafficking of transmembrane through or internalization as observed for the and R. M. P. 1999; PubMed Scopus Google Scholar, J. C. L. M.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, M.J. J.L. Benovic J.L. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). dileucine are located between residues of the BLT1 C-tail. to assess the were for the WT used to and in the BLT1. were to as to motif or in mutant and mutant BLT1 mutant receptors displayed a higher for LTB4 than the WT BLT1 LTB4-induced was increased for the mutant receptor compared with the WT as Interestingly, of the distal dileucine motif to a increase in upon LTB4 of the proximal motif were also observed in a of BLT1 binding with the that the and the mutant receptors higher numbers of binding sites the plasma membrane, but not WT and the BLT1 binding sites for LTB4 these that and are for the observed with the assessed the of WT and mutant BLT1 the plasma by flow Surprisingly, the of COS-7 mutant receptor did not from that of WT BLT1 and were observed the number of was the of the protein was not by of either or of the dileucine and the increased binding of the population of receptors was not the of a higher number of BLT1. it that the distal dileucine motif in LTB4 binding or LTB4 activation of BLT1, by an of the population of receptors in the active of WT and mutant in a When basal activity of the receptors was in of in the absence of LTB4, the and mutant receptors an increase in constitutive a increase in basal compared with the WT BLT1 the basal of the BLT1 did not from the observed with the WT BLT1. the of BLT1 mutant receptors did not R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and not The for BLT1 of activated GPCRs is generally to receptor by arrestin binding and internalization via that BLT1 in a and in cells, but of to receptor the extent of BLT1 endocytosis by flow analysis of receptor the plasma in with WT BLT1 endocytosis in to the mutant receptor, did not Furthermore, the distal dileucine motif was to endocytosis of BLT1 the proximal dileucine motif was not in this and of WT and mutant in a Molecular used modeling to into the of the dileucine located within the C-tail of BLT1. in A and a model of the BLT1. The bovine rhodopsin was used as and modeling was performed as described with the bovine rhodopsin BLT1 a α-helix to helix the dileucine located on the same of this with the proximal motif the of the helix and the distal Leu304-Leu305 motif the of the helix that this model the inactive of the BLT1, in the of rhodopsin the receptor was in inactive of the model that Leu304-Leu305 are in a hydrophobic core with hydrophobic residues in helix VIII and in and in helix in hydrophobic core in stabilizing the inactive of the receptor. is structural determinants and trafficking of BLT1, the high affinity receptor for this that a motif (Leu304-Leu305) located in the C-tail of BLT1 receptor internalization and the numbers of binding sites for of GPCRs specific in signal transduction and and receptor a of this superfamily of BLT1 of these that as sorting and located in the intracellular and residues located within the C-tail of the receptor and C-tail sorting for BLT1 BLT1 (G291stop) an increased number of binding sites for as as signal transduction in to LTB4 R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google internalization was compared with The observed pharmacological from of phosphorylation sites or dileucine involvement of the the C-tail of or phosphorylation sites their to the did not of the WT BLT1 binding and activation it that structural determinants than the sites are for WT BLT1 binding and signal transduction Furthermore, a receptor the WT in of binding characteristics and R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). to on the residues a of residues and sites that BLT1 trafficking. R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google that the sites and are not for the increased binding and activity of the or BLT1. to the dileucine located in this of the and were in the observed with the BLT1. are GPCRs, are in protein internalization and into specific of the T. Annu. Rev. Cell Dev. Biol. 1999; 15: 705-732Crossref PubMed Scopus (425) Google Scholar, A. Biochemistry. 2001; PubMed Scopus Google Scholar, F. 1992; Full Text PDF PubMed Scopus Google Scholar, S. J. Cell Biol. 1995; PubMed Scopus Google Scholar). are as sorting to the F. 1992; Full Text PDF PubMed Scopus Google or to the S. J. Cell Biol. 1995; PubMed Scopus Google and have been in trafficking and endocytosis of transmembrane T. Annu. Rev. Cell Dev. Biol. 1999; 15: 705-732Crossref PubMed Scopus (425) Google Scholar, R. M. P. 1999; PubMed Scopus Google Scholar, A. Biochemistry. 2001; PubMed Scopus Google Scholar). that of the distal dileucine (Leu304-Leu305) motif in a mutant BLT1 with a higher number of binding sites on the similar to was observed for the and for the BLT1 the mutant BLT1 a increase in the number of binding The signal transduction observed with the and to a higher number of receptors on the R. R. A. M. Mol. Pharmacol. 1998; PubMed Scopus Google that a dileucine sequence and an in the C-tail of the receptor was for BLT1 in or were were expressed the plasma membrane, despite numbers of binding suggesting that the dileucine motif have in Interestingly, the hydrophobic are in as in the BLT1 has been proposed that sorting of endocytosis and is via similar K. J.A. I. Full Text PDF PubMed Scopus Google Scholar). formation a and the to the plasma membrane, is to the this dileucine with the of I. P. T. J. 1998; PubMed Scopus Google the sorting of to the The structural determinants and the BLT1 endocytosis are not but have that BLT1 C-tail is for BLT1 as it is for a number of GPCRs, and that this is of that the C-tail Leu304-Leu305 into within the BLT1 LTB4-induced receptor endocytosis in in BLT1 the proximal dileucine motif (Leu292-Leu293) substitution caused a increase in the number of binding relative of the motif from the was to J. A. D. S. J. Cell Biol. 1996; PubMed Scopus Google Scholar). an relative to a dileucine motif, in the is relative to the have been proposed to exist in from the to are in the of trafficking from the plasma to The latter have been suggested to through phosphorylation of an Ser/Thr E. L. L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google binding has also been for the dileucine motif in the receptor F. Le R. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The proximal dileucine motif in BLT1 is located to the of the this motif to the to are or upon as phosphorylation of a M.J. J.L. Benovic J.L. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. C. J. Cell Biol. PubMed Scopus Google Scholar, C. J. J. J.P. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google the the signal sequence or stabilizing the with the BLT1 distal dileucine motif Leu304-Leu305 of BLT1 C-tail to the population of receptors in the active the number of binding sites for binding sites are the C-tail is or the distal dileucine motif is suggesting that WT BLT1 binding sites in a of the LTB4 binding of the to structural on the distal dileucine motif and a for the characteristics displayed by mutant BLT1, used of the BLT1 on the model of the BLT1 was on the of bovine rhodopsin and was as described M. L. A. J. S. R. P. E. J. Pharmacol. 2002; PubMed Scopus Google Scholar). it that the dileucine are located within helix VIII and that the distal motif is in an hydrophobic core hydrophobic residues in helix VIII the and in helix I. A similar hydrophobic core of bovine rhodopsin in to the that the helix to the this structural have a in stabilizing the inactive of the receptor. has been reported that constitutive activation a higher of conformational to the receptor to the of stabilizing conformational higher of conformational the active mutant to between the or inactive and the higher or active U. J.A. R. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the distal to hydrophobic in the of the model to this inactive of the receptor. the that the the inactive and that the of the on the active state, it that the mutant BLT1 activated or have a of activation than the WT receptor to this that the of activation is or that the population of receptor in the active is is to assess the activity of the receptor in absence of agonist or to increased constitutive activity for the mutant BLT1. the of increased constitutive activity for the mutant receptor, suggesting that this mutant has a of and that the receptor is in the active of the receptor also by the a structural the conformational changes in the active of the receptor. the evidence from of receptor used to the that the mutant BLT1 is activated than the WT receptor in presence of the same of leading to a greater population of receptors in signal transduction Mol. Pharmacol. 2000; PubMed Scopus Google Scholar). Moreover, is suggested to the active of GPCRs and has been to higher affinity of a receptor for ligand J.L. J. J. Mol. Biol. PubMed Scopus Google Scholar). this in mutant BLT1 moderate constitutive activity and a higher number of LTB4 binding the is evidence suggesting that the pharmacological of GPCRs, including BLT1 J.L. J. J. Mol. Biol. PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). the C-tail is not for the of BLT1 J.L. J. J. Mol. Biol. PubMed Scopus Google Scholar). an the involvement of complexes L. F. P. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google agonist the of interactions between receptors and intracellular with the machinery or with BLT1 interactions with intracellular the numbers of LTB4 binding sites by on an distal a with intracellular BLT1 in as and LTB4 receptor conformation is by of the distal dileucine motif, the interactions are or of the BLT1 C-tail with or did not the of BLT1 R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and not latter that helix VIII is not with the is that helix VIII high affinity sites for the and upon activation of the receptor, the of this helix high affinity located in the cytoplasmic Moreover, from bovine rhodopsin that the conformational of helix VIII upon activation is Biochemistry. 1999; 38: PubMed Scopus Google Scholar, K. Farrens Altenbach C. Hubbell W.L. Khorana H.G. Biochemistry. 1996; PubMed Scopus Google Scholar). the of this T. K. M. T. T. J. Biol. Chem. an that the helix VIII and the distal dileucine motif of BLT1 in the conformational changes for receptor activation T. K. M. T. T. J. Biol. Chem. Scholar). are in GPCR and these from The presence of helix VIII is interesting it is by in BLT1 to LTB4 R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). that phosphorylation of by also a in BLT1 the C-tail and of the Leu304-Leu305 the substitution of for deletion of the BLT1 C-tail from the receptor pharmacological characteristics compared with WT BLT1, in of ligand binding and basal receptor activity R. Le C. J. M. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, T. K. M. T. T. J. Biol. Chem. Scholar). The latter with the that is located of helix the evidence that a specific dileucine motif in a GPCR helix VIII is in of ligand binding through of the receptor activation for the that internalization of a GPCR on the helix VIII BLT1 through a and but arrestin-independent the for that BLT1

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