Novel type of Gq/11 protein-coupled neurosteroid receptor sensitive to endocrine disrupting chemicals in mast cell line (RBL-2H3).
1 Agonistic neurosteroids, including pregnenolone, dehydroepiandrosterone and its sulfate (DHEAS), caused rapid degranulation in measurements of beta-hexosaminidase (beta-HEX) release from a mast cell line, RBL-2H3. This degranulation was blocked by BSA-conjugated progesterone (PROG-BSA) or 17beta-estradiol, both of which are antagonistic neurosteroids. 2 DHEAS-induced beta-HEX release was blocked by U-73122 or xestospongin C, but not by PTX or EGTA. DHEAS-induced beta-HEX release was also abolished by G(q/11)-AS, but not by G(q/11)-MS. Pharmacological analyses revealed that the neurosteroids stimulated a putative membrane receptor through activation of the novel G(q/11) and phospholipase C. 3 While representative endocrine-disrupting chemicals (EDCs) did not show any degranulation or nocifensive actions by themselves, they blocked the DHEAS-induced degranulation. 4 The binding of a PROG-BSA-fluorescein isothiocyanate conjugate (PROG-BSA-FITC) to cells was inhibited by neurosteroids and EDCs. 5 In the algogenic-induced biting and licking responses test, DHEAS caused agonistic nocifensive actions in a dose-dependent manner between 1 and 10 fmol (i.pl.). DHEAS-induced nocifensive actions were abolished by PROG-BSA or nonylphenol. 6 Taken together, these results suggest that a G(q/11)-coupled neurosteroid receptor may regulate the neuroimmunological activity related to sensory stimulation and that some EDCs have antagonistic actions for this receptor.
Mizota
Kaori
K
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Yoshida
Akira
A
Uchida
Hitoshi
H
Fujita
Ryousuke
R
Ueda
Hiroshi
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002417:Cattle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D015471:Leukemia, Basophilic, Acute / Q000378:metabolism / Q000473:pathology; D047028:Macrocyclic Compounds; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009619:Nociceptors / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D037342:Pertussis Toxin / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011284:Pregnenolone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D011987:Receptors, Steroid / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000737:chemistry; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D004963:Estrenes; D047028:Macrocyclic Compounds; D016376:Oligonucleotides, Antisense; D010080:Oxazoles; D010636:Phenols; D010726:Phosphodiesterase Inhibitors; D011760:Pyrrolidinones; D011987:Receptors, Steroid; C108644:xestospongin A; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D012710:Serum Albumin, Bovine; D003687:Dehydroepiandrosterone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; D011284:Pregnenolone; C025256:nonylphenol; D037342:Pertussis Toxin; D010738:Type C Phospholipases; D001619:beta-N-Acetylhexosaminidases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D016650:Fluorescein-5-isothiocyanate