Human Myometrial Quiescence and Activation during Gestation and Parturition Involve Dramatic Changes in Expression and Activity of Particulate Type II (RIIα) Protein Kinase A Holoenzyme

There are substantial data indicating that components of the cAMP-signaling pathway are differentially expressed in the human myometrium during pregnancy. The effects of cAMP in most tissues and cell types are mainly modulated via protein kinase A, a heterotetrameric protein complex consisting of tw...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2003-05, Vol.88 (5), p.2194-2205
Main Authors: MacDougall, Malcolm. W. J, Europe-Finner, G. Nicholas, Robson, Stephen. C
Format: Article
Language:English
Subjects:
A Kinase Anchor Proteins
Adaptor Proteins, Signal Transducing
Adult
Biological and medical sciences
Blotting, Western
Carrier Proteins - metabolism
Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
Cyclic AMP-Dependent Protein Kinase Type II
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
DNA-Binding Proteins - metabolism
Female
Fundamental and applied biological sciences. Psychology
Gene Expression
Gestational Age
Hormone metabolism and regulation
Humans
Immunohistochemistry
Immunosorbent Techniques
Intracellular Signaling Peptides and Proteins
Middle Aged
Myometrium - enzymology
Nuclear Proteins - metabolism
Parturition
Phosphorylation
Pregnancy
Pregnancy. Parturition. Lactation
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - analysis
Vertebrates: reproduction
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Summary:There are substantial data indicating that components of the cAMP-signaling pathway are differentially expressed in the human myometrium during pregnancy. The effects of cAMP in most tissues and cell types are mainly modulated via protein kinase A, a heterotetrameric protein complex consisting of two regulatory (R) and two catalytic (C) subunits. In the studies presented here, we used specific antibodies in Western blotting/immunoprecipitation, RT-PCR, and functional protein kinase A (PKA) phosphorylation assays to determine the PKA holoenzymes that are expressed in the human myometrium throughout pregnancy and labor. We report that as early as the second trimester of pregnancy, there is a significant increase in expression of the regulatory RIIα protein subunit of PKA in the myometrium. This increase in protein expression is also mirrored at the mRNA level, indicating transcriptional control throughout pregnancy, whereas during parturition both transcript and protein are significantly decreased. This increase in RIIα protein also resulted in increased particulate PKA activity in the myometrium during gestation, which was subsequently decreased during labor. Two specific A kinase anchoring proteins, AKAP95 and AKAP79, which have high binding affinities for RIIα subunits, were found to form complexes with myometrial RIIα species employing immunoprecipitation assays, but their levels of expression remained uniform in all myometrial tissue samples investigated. Our findings indicate that increased particulate type II PKA activity occurs throughout pregnancy, therefore directing the cAMP quiescence signal to specific subcellular loci within myometrial smooth muscle cells including the contractile machinery at the cytoskeleton; this effect is then removed during parturition.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2002-021862