Activation of protein kinase C by oxytocin inhibits the biological activity of the human myometrial corticotropin-releasing hormone receptor at term

The role of placental CRH in human pregnancy is currently unknown. The myom etrium expresses CRH receptors that during pregnancy become coupled to aden ylate cyclase. Oxytocin (OT) is one of the main regulators of uterine activ ity, acting via activation of the inositol triphosphate pathway. In view of the possible cross-talk between the CRH and OT signal transduction pathway s we have sought to examine in more detail the second messenger mechanisms involved. CRH receptor binding affinity for CRH and activation of adenylate cyclase w ere reduced in the presence of OT in pregnant (at term, but not preterm) hu man myometrium. OT action was mediated via pertussis toxin-sensitive G prot eins, which directly inhibit adenylate cyclase and, via activation of prote in kinase C, phosphorylate the CRH receptor, leading to desensitization. Ac tivation of protein kinase C by OT could be partially inhibited in human pr egnant myometrial cells by OT antagonists (F327 and CAP476; 1 mu M) or phos pholipase C inhibitors (U73122; 10 mu M). These results suggest that in term myometrium, CRH receptor function is mod ulated by OT, leading to reduced biological activity, lower cAMP levels, an d a subsequent shift, in favor of contractility rather than relaxation.