Guinea pig cysteinyl leukotriene receptor 2 (gpCysLT2) mediates cell proliferation and intracellular calcium mobilization by LTC4 and LTD4.
We cloned and pharmacologically characterized the guinea pig cysteinyl leukotriene (CysLT) 2 receptor (gpCysLT2). gpCysLT2 consists of 317 amino acids with 75.3%, 75.2%, 73.3% identity to those of humans, mice and rats, respectively. The gpCysLT2 gene is highly expressed in the lung, moderately in eosinophils, skin, spleen, stomach, colon, and modestly in the small intestine. CysLTs accelerated the proliferation of gpCysLT2-expressing HEK293. Leukotriene C4 (LTC4) and Leukotriene D4 (LTD4) enhanced the cell proliferation higher than Bay-u9773, a CysLT2 selective partial agonist and a nonselective antagonist for CysLT receptors. Bay-u9773 did not antagonize the cell proliferation by LTC4 and LTD4. Despite the equipotency of the mitogenic effect among these chemicals, calcium mobilization (CM) levels were variable (LTC4> LTD4>> Bay-u9773), and Bay-u9773 antagonized the CM by LTC4. Moreover, the Gi/o inhibitor pertussis toxin perfectly inhibited agonist-induced cell proliferation. These results reveal that cell proliferation via CysLT2 signaling was mediated by Gi/o signaling but independent of calcium mobilization.
Ito
Yoshiyuki
Y
Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University, Tsu, Japan.
Hirano
Minoru
M
Umemoto
Noriko
N
Zang
Liqing
L
Wang
Zhipeng
Z
Oka
Takehiko
T
Shimada
Yasuhito
Y
Nishimura
Yuhei
Y
Kurokawa
Ichiro
I
Mizutani
Hitoshi
H
Tanaka
Toshio
T
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004804:Eosinophils / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000196:embryology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010537:Peritoneum; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018077:Receptors, Leukotriene / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013189:SRS-A / Q000031:analogs & derivatives / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
C071435:BAY u9773; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D013189:SRS-A; D017997:Leukotriene C4; D017998:Leukotriene D4; C412375:cysteinyl leukotriene receptor 2; D037342:Pertussis Toxin; D002118:Calcium