Binding Studies with Rat Myometrial and Mammary Gland Membranes on Effects of Manganese on Relative Affinities of Receptors for Oxytocin Analogs*

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Abstract
Mg2+ increases the potency of oxytocin (OT) analogs in stimulating uterine contractions. Generally, the enhancing effects of Mg2+ are inversely related to the potency of the peptide. To determine the site of metal ion action, we measured the effects of Mn2+, another potentiating metal ion, on the ability of a series of peptides to inhibit the binding of [3H]OT to receptor sites on both uterine myometrial and mammary gland plasma membranes. The analogs used in this study were derivatives of 7-glycine oxytocin, which is about 10 times more active when the Mg2+ concentration in the uterine smooth muscle bath is increased from 0 to 0.5 mM. We found a generally good correlation between the ability of the analogs to inhibit [3H]OT binding to both receptor systems and their biological potencies. An increase in Mn2+ concentration from 1 to 10 mM enhanced the affinity of uterine membranes for the analogs, in inverse proportion to their potencies. This selective enhancement occurred regardless of the structural modification of the peptide. These results suggest that the metal ion effect occurs at the receptor level nad is not a property of the peptide per se. In contrast to the uterus, the affinities of mammary gland receptors for two low potency analogs were unaffected by increased Mn2+ concentration. The mechanisms of the metal ion effect are not entirely understood, but it appears that Mn2+ allows the conformation of the myometrial receptor to adapt to less well-fitting ligands. Although the metal ion effects on mammary gland receptors are more difficult to interpret, it is clear that uterine and mammary gland receptors are different with respect to the mechanisms of interaction with peptides.