Antidiabetic sulfonylurea enhances secretagogue-induced adrenocorticotropin secretion and proopiomelanocortin gene expression in vitro

The presence of high-affinity binding sites for antidiabetic sulfonylureas (SUs) and the expression of SU receptor (SUR) messenger RNA in the adenohyp ophyseal cells have recently been reported. In this study, we examined the effects of SU on POMC gene expression and ACTH secretion using the AtT20PL cell line, a subclone of AtT20 in which the rat POMC 5'-promoter-luciferase fusion gene was stably incorporated. A representative SU glibenclamide inh ibited the basal POMC 5'-promoter activity. In contrast, glibenclamide enha nced forskolin- or CRH-induced POMC expression in a dose-dependent manner. Interestingly, the latter effect was not observed under treatment with 3-is obutyl-1-methylxanthine, a nonselective phosphodiesterase inhibitor. Furthe rmore, diazoxide, an opener of the ATP-sensitive K+ channel, only antagoniz ed the suppressive effect of glibenclamide. Lastly, RT-PCR analysis showed that mouse SUR (but not SURE) messenger RNA was expressed in this cell line . These results suggest that, in AtT20PL cells, SU has dual effects, i.e. a suppressive effect on basal POMC expression through diazoxide-sensitive (A TP-sensitive) K+-channel-mediated mechanism, and an enhancing effect on cAM P/protein kinase A-stimulated POMC expression through a different mechanism (probably mediated by phosphodiesterase). To our knowledge, this is the fi rst report showing the effect of SU on the expression of the anterior pitui tary hormone gene.