Regulation of calcitonin gene-related peptide receptors in the rat uterus during pregnancy and labor and by progesterone

Calcitonin gene-related peptide (CGRP) is a potent smooth muscle relaxant i n a variety of tissues. We recently demonstrated that CGRP relaxes uterine tissue during pregnancy but not during labor. In the present study we exami ned whether uterine I-125-CGRP binding and immunoreactive CGRP receptors ar e regulated by pregnancy and labor and by sex steroid hormones. We found th at I-125-CGRP binding to membrane preparations from uteri was elevated duri ng pregnancy and decreased during labor and postpartum. Changes in immunore active CGRP receptors were similar to the changes in I-125-CGRP binding in these tissues, suggesting pregnancy-dependent regulation of CGRP receptor p rotein. CGRP receptors were elevated by Day 7 of gestation, and a precipito us decrease in these receptors occurred on Day 22 of gestation prior to the onset of labor. Both I-125-CGRP-binding and immunofluorescence studies ind icated that CGRP receptors were localized to myometrial cells. Hormonal control of uterine CGRP receptors was assessed by the use of antip rogesterone RU-486, progesterone, and estradiol-17 beta. RU-486 induced a d ecrease in uterine CGRP receptors during pregnancy (Day 19). On the other h and, progesterone prevented the fall in uterine CGRP receptors at term (Day 22).; In addition, progesterone also increased uterine CGRP receptors in n onpregnant, ovariectomized rats, while estradiol had no effects. These horm one-induced changes in uterine CGRP receptors were demonstrated by I-125-CG RP-binding, Western immunoblotting, and immunolocalization methods. These results indicate that CGRP receptors and CGRP binding in the rat uter us are increased with pregnancy and decreased at term. These receptors are localized to the myometrial cells, and progesterone is required for maintai ning CGRP receptors in the rat uterus. Thus, the inhibitory effects of CGRP on uterine contractility are mediated through the changes in CGRP receptor s and may play a role in uterine quiescence during pregnancy.