Bradykinin-activated contractile signalling pathways in human myometrial cells are differentially regulated by arrestin proteins

• Bradykinin activates Ca2+ signals via bradykinin B2 receptors in myometrial cells.
• Arrestin2/3 depletion attenuates bradykinin B2 receptor desensitisation.
• Arrestin2/3 depletion enhanced bradykinin B2 receptor ERK1/2 signalling.
• Arrestin3 depletion increased and prolonged bradykinin-stimulated p38 MAPK signals.
• Bradykinin activates pro-contractile signalling pathways in the human myometrium.

Bradykinin is associated with infections and inflammation, which given the strong correlation between uterine infection and preterm labour may imply that it could play a role in this process. Therefore, we investigated bradykinin signalling, and the roles that arrestin proteins play in their regulation in human myometrial cells. Bradykinin induced rapid, transient intracellular Ca2+ increases that were inhibited following B2 receptor (B2R) antagonism. Arrestin2 or arrestin3 depletion enhanced and prolonged bradykinin-stimulated Ca2+ responses, and attenuated B2R desensitisation. Knockdown of either arrestin enhanced B2R-stimulated ERK1/2 signals. Moreover, depletion of either arrestin elevated peak-phase p38-MAPK signalling, yet only arrestin3 depletion prolonged B2R-induced p38-MAPK signals. Arrestin2-knockdown augmented bradykinin-induced cell movement. Bradykinin stimulates pro-contractile signalling mechanisms in human myometrial cells and arrestin proteins play key roles in their regulation. Our data suggest bradykinin not only acts as an utertonin, but may also have the potential to enhance the contractile environment of the uterus.

Graphical AbstractBradykinin-stimulates pro-contractile signalling pathways in human myometrial smooth muscle cells which induces cellular movement. The bradykinin-activated signalling pathways regulated by arrestin proteins are shown alongside potential pathways by which bradykinin may induce a pro-contractile phenotype through MAPK signalling are displayed as ‘?’.Figure optionsDownload high-quality image (54 K)Download as PowerPoint slide