Activation of Protein Kinase C by Oxytocin Inhibits the Biological Activity of the Human Myometrial Corticotropin-Releasing Hormone Receptor at Term*

Feb 2, 1999Endocrinology

Oxytocin activates protein kinase C to reduce activity of the human labor hormone receptor at term

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Abstract

CRH receptor function is modulated by oxytocin in term human myometrium, leading to reduced biological activity.

CRH receptor binding affinity and adenylate cyclase activation decreased in the presence of oxytocin in term pregnant myometrium.
Oxytocin's effect is mediated through pertussis toxin-sensitive G proteins that inhibit adenylate cyclase.
The action of oxytocin results in phosphorylation of the CRH receptor, which may lead to receptor desensitization.
Activation of protein kinase C by oxytocin can be partially inhibited by certain OT antagonists and phospholipase C inhibitors.
These changes are associated with lower cAMP levels and a shift towards enhanced uterine contractility.

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The role of placental CRH in human pregnancy is currently unknown. The myometrium expresses CRH receptors that during pregnancy become coupled to adenylate cyclase. Oxytocin (OT) is one of the main regulators of uterine activity, acting via activation of the inositol triphosphate pathway. In view of the possible cross-talk between the CRH and OT signal transduction pathways we have sought to examine in more detail the second messenger mechanisms involved. CRH receptor binding affinity for CRH and activation of adenylate cyclase were reduced in the presence of OT in pregnant (at term, but not preterm) human myometrium. OT action was mediated via pertussis toxin-sensitive G proteins, which directly inhibit adenylate cyclase and, via activation of protein kinase C, phosphorylate the CRH receptor, leading to desensitization. Activation of protein kinase C by OT could be partially inhibited in human pregnant myometrial cells by OT antagonists (F327 and CAP476; 1 microM) or phospholipase C inhibitors (U73122; 10 microM). These results suggest that in term myometrium, CRH receptor function is modulated by OT, leading to reduced biological activity, lower cAMP levels, and a subsequent shift in favor of contractility rather than relaxation.

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Activation of Protein Kinase C by Oxytocin Inhibits the Biological Activity of the Human Myometrial Corticotropin-Releasing Hormone Receptor at Term*

Abstract

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