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 adenohypophyseal 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 inhibited the basal POMC 5'-promoter activity. In contrast, glibenclamide enhanced forskolin- or CRH-induced POMC expression in a dose-dependent manner. Interestingly, the latter effect was not observed under treatment with 3-isobutyl-1-methylxanthine, a nonselective phosphodiesterase inhibitor. Furthermore, diazoxide, an opener of the ATP-sensitive K+ channel, only antagonized the suppressive effect of glibenclamide. Lastly, RT-PCR analysis showed that mouse SUR (but not SUR2) 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 (ATP-sensitive) K+-channel-mediated mechanism, and an enhancing effect on cAMP/protein kinase A-stimulated POMC expression through a different mechanism (probably mediated by phosphodiesterase). To our knowledge, this is the first report showing the effect of SU on the expression of the anterior pituitary hormone gene.
Morishita
M
M
First Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Iwasaki
Y
Y
Yamamori
E
E
Nomura
A
A
Mutsuga
N
N
Yoshida
M
M
Asai
M
M
Oiso
Y
Y
Saito
H
H
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D005576:Colforsin / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology; D004232:Diuretics; D015870:Gene Expression / Q000187:drug effects*; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology; D013268:Stimulation, Chemical; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
D004232:Diuretics; D007004:Hypoglycemic Agents; D049993:Sodium Chloride Symporter Inhibitors; D013453:Sulfonylurea Compounds; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003981:Diazoxide; D005905:Glyburide