Synthesis and evaluation of lysophosphatidylserine analogues as inducers of mast cell degranulation. Potent activities of lysophosphatidylthreonine and its 2-deoxy derivative.
In response to various exogenous stimuli, mast cells (MCs) release a wide variety of inflammatory mediators stored in their cytoplasmic granules and this release initiates subsequent allergic reactions. Lysophosphatidylserine (lysoPS) has been known as an exogenous inducer to potentiate histamine release from MCs, though even at submicromolar concentrations. In this study, through SAR studies on lysoPS against MC degranulation, we identified lysoPT, a threonine-containing lysophospholipid and its 2-deoxy derivative as novel strong agonists. LysoPT and its 2-deoxy derivative induced histamine release from MCs both in vitro and in vivo at a concentration less than one-tenth that of lysoPS. Notably, lysoPT did not activate a recently proposed lysoPS receptor on MCs, GPR34, demonstrating the presence of another undefined receptor reactive to both lysoPS and lysoPT that is involved in MC degranulation. Thus, the present strong agonists, lysoPT and its 2-deoxy derivative, will be useful tools to understand the mechanisms of lysoPS-induced activation of degranulation of MCs.
Iwashita
Masazumi
M
Laboratory of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Makide
Kumiko
K
Nonomura
Taro
T
Misumi
Yoshimasa
Y
Otani
Yuko
Y
Ishida
Mayuko
M
Taguchi
Ryo
R
Tsujimoto
Masafumi
M
Aoki
Junken
J
Arai
Hiroyuki
H
Ohwada
Tomohiko
T
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D020404:Glycerophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology; D006632:Histamine / Q000378:metabolism; D018836:Inflammation Mediators; D008246:Lysophospholipids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D051381:Rats; D013329:Structure-Activity Relationship; D013912:Threonine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D020404:Glycerophospholipids; D018836:Inflammation Mediators; D008246:Lysophospholipids; C025059:lysophosphatidylserine; D013912:Threonine; D006632:Histamine