Serotonin-mediated 5-HT2 receptor gene regulation in rat myometrial smooth muscle cells.
Serotonin (5-hydroxytryptamine; 5-HT) has recently been shown to induce collagenase production in myometrial smooth muscle cells (Jeffrey et al. (1991) J. Cell. Physiol. 146, 399-406) by activating transcription of the collagenase gene (Wilcox et al. (1992) J. Biol. Chem. 267, 20752-20757) following an interaction with the 5-HT2 receptor (Rydelek-Fitzgerald et al. (1993) Mol. Cell. Endocrinol. 91, 67-74). These studies were performed to investigate factors controlling the regulation of 5-HT2 receptors in these cells. Northern blot analysis indicates that serotonin increases levels of 5-HT2 receptor mRNA in cells by approximately 4-fold. Detectable increases in mRNA levels occur within 2 h after administration of serotonin with maximal levels occurring after 12 h. The 5-HT2 receptor antagonists, ketanserin and spiperone, inhibit the serotonin-mediated increase in receptor mRNA. Selective 5-HT2 receptor agonists ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) and quipazine) mimic the effect of serotonin, whereas 5-HT1 and 5-HT3 receptor agonists ((+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT), 1-(3-chlorophenyl)piperazine dihydrochloride (mCPP), m-phenylbiguanide) have no effect. These data demonstrate that serotonin induces an increase in 5-HT2 receptor mRNA by interacting with the 5-HT2 receptor itself. Nuclear run-on analysis revealed that serotonin increases the initiation of 5-HT2 receptor mRNA synthesis. Moreover, the protein synthesis inhibitor, cycloheximide, prevents the induction of the mRNA for the receptor, demonstrating that serotonin-dependent increases in 5-HT2 receptor transcription require de novo protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Rydelek-Fitzgerald
L
L
Department of Pharmacology and Toxicology, Albany Medical College, NY 12208.
Wilcox
B D
BD
Teitler
M
M
Jeffrey
J J
JJ
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007650:Ketanserin / Q000494:pharmacology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D009215:Myometrium / Q000166:cytology / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011814:Quipazine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000235:genetics*; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013134:Spiperone / Q000494:pharmacology; D013469:Sulpiride / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000662:Amphetamines; D001645:Biguanides; D010879:Piperazines; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D011814:Quipazine; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D013469:Sulpiride; C065734:1-(3-chlorophenyl)biguanide; D007650:Ketanserin; D003513:Cycloheximide; D017258:Medroxyprogesterone Acetate; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; C015068:1-(3-chlorophenyl)piperazine