The oxytocin receptor (OTR) is a Gq-coupled GPCR that fulfills central and peripheral functions, including myometrial contractions at labor. The great diversity of the expression sites and proposed functions of the OTR is paralleled by a diversity of its signaling pathways, many of which have still remained unexplored.

By means of a phosphoproteomics approach, we have detected that OTR stimulation induces activation of eukaryotic translation factor eEF2, a key regulator of protein synthesis, thus defining a novel mechanism by which OT assumes a trophic function. We found that this effect is not mediated by any of the known pathways known to induce eEF2 dephosphorylation (mTOR, ERK1/2 or p38) but by protein kinase C.

Using phosphoERK antibodies, we discovered that OTR stimulation induced not only ERK1/2 activation but also phosphorylation of "big MAP kinase1" or ERK5. ERK5 is part of a distinct MAPK cascade, promotes expression of the myosin light chain gene and plays an obligatory role in muscle cell development. ERK5 knock down by specific siRNAs led to a significant reduction in oxytocin (OT)-induced COX-2 expression, prostaglandin F2alpha secretion and myometrial contraction, indicating that ERK5 is an essential mediator of OT-mediated prostaglandin secretion and contractions. Preliminary evidence indicates that ERK5 activation involves both G protein-dependent and –independent pathways.

The OTR interacts also with other GPCRs co-expressed in myometrial cells. Heterodimerization with the (2 adrenergic receptor ((2AR) was supported by BRET experiments. We also obtained evidence that this interaction has functional consequences: (2AR antagonists are able to modulate allosterically OTR signalling and OTR trafficking and, vice versa, an OT antagonist can modulate (2AR signalling.