Effects of loperamide and other opioid-related substances on the transcriptional regulation of the rat pro-opiomelanocortin gene in AtT20 cells.
Although opioid peptides are involved in the regulation of the hypothalamic-pituitary-adrenal axis, their role in pro-opiomelanocortin (POMC) gene expression at the pituitary level is not known. We therefore examined the effects of opioid receptor agonists, including recently discovered endogenous opioid peptides, on POMC gene expression using the AtT20PL cell line, a subclone of AtT20 in which the rat POMC 5'-promoter-luciferase fusion gene was stably incorporated. The endogenous mu-opioid receptor agonists endomorphin 1 and 2 had no effect on either basal or corticotropin-stimulating-hormone-induced POMC expression. This was also the case with the delta-agonist BUBUC, the kappa-agonist U50488H and the orphan receptor agonist orphanin FQ. In contrast, the synthetic mu-agonist loperamide significantly inhibited basal and yet enhanced cAMP-induced POMC expression. The inhibitory effect of loperamide was mimicked by the calmodulin antagonist W7 and antagonized by the calcium channel blocker nifedipine, whereas neither the inhibitory nor the enhancing effect of loperamide was influenced by the opioid antagonist naloxone. These results suggest that the synthetic mu-agonist loperamide has a modulatory effect on the 5'-promoter activity of the POMC gene. This effect does not seem to be mediated through the classical mu-opioid receptor but rather in part through a calcium/calmodulin-related mechanism.
Nomura
A
A
First Department of Internal Medicine, Nagoya University School of Medicine and Hospital, Nagoya, Japan.
Iwasaki
Y
Y
Aoki
Y
Y
Yamamori
E
E
Mutsuga
N
N
Yoshida
M
M
Asai
M
M
Oiso
Y
Y
Saito
H
H
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D008139:Loperamide / Q000494:pharmacology*; D051379:Mice; D009270:Naloxone / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D000097629:Nociceptin
D005576:Colforsin; D008139:Loperamide; D009270:Naloxone; D009543:Nifedipine; D009842:Oligopeptides; D018847:Opioid Peptides; D011333:Pro-Opiomelanocortin; D017450:Receptors, Opioid, mu; D013449:Sulfonamides; D000097629:Nociceptin; C105293:endomorphin 1; C105294:endomorphin 2; C017967:W 7