Changes in cAMP effector predominance are associated with increased oxytocin receptor expression in twin but not infection-associated or idiopathic preterm labour

Angela Yulia,Mark R Johnson,Rachel Tribe,Natasha Singh,Alice J Varley,Kaiyu Lei,Tamas Zakar

doi:10.1371/journal.pone.0240325

Angela Yulia, Mark R Johnson + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0240325

Copy DOI

Journal: PloS one	Publication Date: Nov 30, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: Chelsea and Westminster Hospital, King's College London

Abstract

We previously reported that at term pregnancy, a decline in myometrial protein kinase A (PKA) activity leads to an exchange protein activated by cyclic AMP (Epac1)-dependent increase in oxytocin receptor (OTR) expression, promoting the onset of labour. Here, we studied the changes in the cyclic adenosine monophosphate (cAMP) effector system present in different phenotypes of preterm labour (PTL). Myometrial biopsies obtained from women with phenotypically distinct forms of PTL and the levels of PKA and OTR were examined.Although we found similar changes in the cAMP effector pathway in all forms of PTL, only in the case of twin PTL (T-PTL) was myometrial OTR levels increased in association with these results. Although there were several changes in the mRNA levels of components of the cAMP synthetic pathway, the total myometrial cAMP levels did not change with the onset of any subtype of PTL. With regards to the expression of cAMP-responsive genes, we found that the mRNA levels of 4 of the 5 cAMP-down-regulated genes were increased in T-PTL, similar to our findings in term labour.These data signify that although changes in the cAMP effector system were common to all forms of PTL, only in T-PTL were OTR levels increased. Similarly, the mRNA levels of cAMP-repressed genes were only increased in T-PTL supporting the concept that the decline in PKA levels influences myometrial function driving the onset of T-PTL.

Highlights

Understanding the factors that control the onset of labour is key to our ability to stop and start labour when medically necessary
In T-Preterm labour (PTL) samples, there is no significant difference in mRNA levels (Fig 1A, 1C & 1E), both PKAc and PKAR2α declined at a protein level and Epac1 protein level tended to increase (p = 0.06; Fig 1F)
We observed a decline in the Cyclic AMP (cAMP)/protein kinase A (PKA) system in twin PTL (T-PTL) in association with an increase in oxytocin receptor (OTR) levels and a loss of repression of cAMP repressed genes, as we reported in early term labour [7]

Summary

Introduction

Understanding the factors that control the onset of labour is key to our ability to stop and start labour when medically necessary. Cyclic AMP (cAMP) is widely expressed and acts as a second messenger in intracellular signalling pathways controlling a wide range of cellular functions. In the myometrium, it acts via its primary effector, protein kinase A (PKA), to promote uterine quiescence. The CREM gene encodes the powerful repressor ICER, which negatively feeds back on cAMP-induced transcription [3,5] These transcription factors can all be phosphorylated by many different kinases, for example, CREB is activated by phosphorylation at Ser133 by various signalling pathways including extracellular signal-regulated kinase, and calcium [5,6]. Our group have previously demonstrated that the decline in PKA activity with advancing gestation was supported by demonstrating a reduction in phospho-CREB, with the lowest levels observed at the term established labour group [7]

Methods

Results

Conclusion