Novel type of G q/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 β ‐hexosaminidase ( β ‐HEX) release from a mast cell line, RBL‐2H3. This degranulation was blocked by BSA‐conjugated progesterone (PROG‐BSA) or 17 β ‐estradiol, both of which are antagonistic neurosteroids. 2 DHEAS‐induced β ‐HEX release was blocked by U‐73122 or xestospongin C, but not by PTX or EGTA. DHEAS‐induced β ‐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.British Journal of Pharmacology (2005) 145 , 545–550. doi: 10.1038/sj.bjp.0706213