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Activation of Adenylyl Cyclase in Human Myometrial Smooth Muscle Cells by Neuropeptides¹

The Cecil H. and Ida Green Center for Reproductive Biology Sciences and Departments of Obstetrics-Gynecology and Biochemistry, The University of Texas Southwestern Medical School at Dallas, Texas 75235

Address all correspondence and requests for reprints to: M. Linette Casey, The Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9051. E-mail: casey{at}grnctr.swmed.edu

The levels of intracellular cAMP in human myometrial smooth muscle cells in serum-free medium, or medium that contained FBS (1%, vol/vol), were determined after treatment with the homologous peptides, calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), and amylin, without or with added isobutylmethylxanthine (IBMX). These cells were sensitive to CGRP, responding in a dose-dependent manner, with maximal levels of cAMP being attained with 5 nM CGRP in the presence of IBMX (1 mM). In the absence of IBMX, the level of cAMP attained in cells treated with CGRP (5 nM) (675.3 ± 58.8 pmol•mg protein•15 min; mean ± SEM, n = 3) was approximately 90x that in nontreated cells (7.5 ± 0.4 pmol•mg protein•15 min). The level of cAMP in myometrial cells treated with CGRP (5 nM) + IBMX (1 mM), 1998 ± 420 pmol•mg protein•15 min, was 29x that in cells treated with IBMX alone (69.2 ± 10.2). The maximum level of cAMP achieved by treatment with ADM + IBMX was similar to that with CGRP + IBMX, but the dose of ADM required (1 µM) was approximately 200x that of CGRP. Amylin amide also caused an increase in cAMP but with considerably less potency; at a concentration of 500 nM, amylin amide + IBMX effected a 2.3-fold increase in cAMP relative to IBMX alone. CGRP_8–37, an antagonist of CGRP via the CGRP₁ receptor, inhibited the action of CGRP, ADM, and amylin in myometrial cells. Treatment with [cys(ACM)_2–7]-CGRP, a CGRP₂ receptor agonist, did not cause an increase in the levels of cAMP in these cells. These findings are indicative that CGRP, ADM, and amylin act via that the CGRP₁ receptor in human myometrial cells. Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide also caused a dose-dependent increase in cAMP in myometrial cells. The findings of this study are indicative that multiple neuropeptides, acting by way of heptahelical receptors linked to the G_s-subunit of the G-proteins, may contribute to the maintenance of uterine quiescence during some period of human pregnancy.

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