Novel binding sites of 15-deoxy-Delta12,14-prostaglandin J2 in plasma membranes from primary rat cortical neurons.
15-Deoxy-Delta12,14-prostaglandin J2 (15d-Delta12,14-PGJ2) is an endogenous ligand for a nuclear peroxysome proliferator activated receptor-gamma (PPAR). We found novel binding sites of 15d-Delta12,14-PGJ2 in the neuronal plasma membranes of the cerebral cortex. The binding sites of [3H]15d-Delta12,14-PGJ2 were displaced by 15d-Delta12,14-PGJ2 with a half-maximal concentration of 1.6 microM. PGD2 and its metabolites also inhibited the binding of [3H]15d-Delta12,14-PGJ2. Affinities for the novel binding sites were 15d-Delta12,14-PGJ2 > Delta12-PGJ2 > PGJ2 > PGD2. Other eicosanoids and PPAR agonists did not alter the binding of [3H]15d-Delta12,14-PGJ2. In primary cultures of rat cortical neurons, we examined the pathophysiologic roles of the novel binding sites. 15d-Delta12,14-PGJ2 triggered neuronal cell death in a concentration-dependent manner, with a half-maximal concentration of 1.1 microM. The neurotoxic potency of PGD2 and its metabolites was also 15d-Delta12,14-PGJ2 > Delta12-PGJ2 > PGJ2 > PGD2. The morphologic and ultrastructural characteristics of 15d-Delta12,14-PGJ2-induced neuronal cell death were apoptotic, as evidenced by condensed chromatin and fragmented DNA. On the other hand, we detected little neurotoxicity of other eicosanoids and PPAR agonists. In conclusion, we demonstrated that novel binding sites of 15d-Delta12,14-PGJ2 exist in the plasma membrane. The present study suggests that the novel binding sites might be involved in 15d-Delta12,14-PGJ2-induced neuronal apoptosis.
Yagami
Tatsurou
T
Discovery Research Laboratories, Shionogi and Co., Ltd., 12-4, Sagisu 5-Choume, Fukushima-ku, Osaka 553-0002, Japan. VZX00556@nifty.com
Ueda
Keiichi
K
Asakura
Kenji
K
Takasu
Nobuo
N
Sakaeda
Toshiyuki
T
Itoh
Naohiro
N
Sakaguchi
Gaku
G
Kishino
Junji
J
Nakazato
Hitosi
H
Katsuyama
Yoshihiko
Y
Nagasaki
Tohru
T
Okamura
Noboru
N
Hori
Yozo
Y
Hanasaki
Kohji
K
Arimura
Akinori
A
Fujimoto
Masafumi
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002843:Chromatin / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014316:Tritium
C477819:15-deoxyprostaglandin J2; D002843:Chromatin; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014316:Tritium; D015230:Prostaglandin D2