Exploring the pharmacology of the leukotriene B4 receptor BLT1, without the confounding effects of BLT2.
Most previous studies of leukotriene B4 (LTB4) pharmacology using primary leukocyte cultures and myeloid cell lines do not differentiate between leukotriene BLT1 and BLT2 receptor activation because both receptors are often expressed by these cells. Here we show that in HeLa cells expressing BLT1 but not BLT2 receptors, BLT1 receptor activation resulted in IP3 mediated calcium release from intracellular stores initially, followed by calcium influx through cell membrane channels. BLT1 calcium signalling was sensitive to the activity of protein kinase C (PKC), protein kinase A (PKA) and protein-tyrosine kinases (PTKs), as well as changes in membrane cholesterol levels and treatments that are known to disrupt normal membrane physiology and/or lipid rafts. Inhibition of MAP kinases, Rho-associated kinases, or phosphoinositol-3-kinases (PI3K) had no effect on BLT1 receptor induced calcium signalling, and the receptor was insensitive to the redox state of the extracellular compartment.
Sabirsh
Alan
A
Medical Biochemistry and Biophysics, Karolinska Institute, MBB, Kemi II, 171 77 Stockholm, Sweden. Alan.Sabirsh@mbb.ki.se
Bristulf
Jesper
J
Owman
Christer
C
D001896:Boron Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D005233:Fatty Alcohols / Q000494:pharmacology; D006018:Glycols / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics; D011433:Propranolol / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
D001896:Boron Compounds; D002121:Calcium Channel Blockers; D004963:Estrenes; D005233:Fatty Alcohols; D006018:Glycols; D007093:Imidazoles; D007211:Indoles; C485878:LTB4R2 protein, human; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D018102:Receptors, Leukotriene B4; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C062137:U 75302; D019284:Thapsigargin; D009532:Nickel; D011433:Propranolol; C109986:2-aminoethoxydiphenyl borate; D003620:Dantrolene; D019311:Staurosporine; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D009543:Nifedipine; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium