Transcription factors regulated by cAMP in smooth muscle of the myometrium at human parturition

Jonathan K.H Li,Rachel M Tribe,Mark R Johnson,Pei F Lai

doi:10.1042/bst20201173

Abstract

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium.

Highlights

In the uterus, smooth muscle cells of the myometrium are maintained in a quiescent state throughout pregnancy to facilitate fetal growth and maturation
Future efforts in identifying ways to harness the uterine pro-quiescent effects of cyclic adenosine monophosphate (cAMP) will need to focus on the importance of spatio-temporal factors of cAMP signalling, as well as the activities of cAMP-binding proteins other than PKA, in mSMCs
Open access for this article was enabled by the participation of Imperial College London in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC

Summary

Introduction

Smooth muscle cells of the myometrium (mSMCs) are maintained in a quiescent state throughout pregnancy to facilitate fetal growth and maturation. Future efforts in identifying ways to harness the uterine pro-quiescent effects of cAMP will need to focus on the importance of spatio-temporal factors of cAMP signalling, as well as the activities of cAMP-binding proteins other than PKA, in mSMCs. A better understanding of how cAMP controls myometrial contractions will aid the development of therapies that reduce maternal and neonatal risk from obstetric complications, which includes preterm birth.

Results

Conclusion