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)