Serotonin-dependent collagenase induction in rat myometrial smooth muscle cells: mediation by the 5-HT2 receptor.
Recent studies have shown that serotonin (5-hydroxytryptamine; 5-HT) is required for the induction of interstitial collagenase in cultured rat and human myometrial smooth muscle cells. The present study was performed to determine which serotonin receptor subtype mediates the induction of collagenase in these cells. [125I]DOI ((+/- )-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane), a 5-HT2 receptor agonist radioligand, bound specifically to sites in myometrial cell membranes, and exhibited binding characteristics essentially identical to those observed with brain 5-HT2 receptors. Radioligands selective for other serotonin receptor subtypes (5-HT1 and 5-HT3) failed to yield detectable binding. Northern blot analysis demonstrated the presence of 5-HT2 mRNA in the uterine smooth muscle cell cultures, whereas transcripts for 5-HT1A and 5-HT1C receptors were not detectable. Moreover, RT-PCR indicated that 5-HT2 receptor mRNA is present in freshly isolated uterine tissue as well. Selective antagonists of the 5-HT2 receptor, ketanserin and spiperone, displayed concentration-dependent inhibition of serotonin-mediated collagenase induction in the myometrial cultures. These antagonists yielded IC50 values of 4.7 nM and 2.7 nM respectively, characteristic of values expected from a 5-HT2 receptor-mediated response. In addition, a number of selective 5-HT2 receptor agonists (quipazine, alpha-methyl-serotonin, DOI) mimicked the ability of serotonin to induce collagenase production, whereas compounds selective for 5-HT1 and 5-HT3 receptor subtypes had little effect.(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
D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D017364:Collagenases / Q000096:biosynthesis*; D005260:Female; D007457:Iodine Radioisotopes; D007650:Ketanserin / Q000494:pharmacology; D008969:Molecular Sequence Data; D009215:Myometrium / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D013134:Spiperone / Q000494:pharmacology
D000662:Amphetamines; D007457:Iodine Radioisotopes; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D013134:Spiperone; D007650:Ketanserin; D017364:Collagenases; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine