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This Article Full Text Full Text (PDF) All Versions of this Article: 295/3/G493    most recent ajpgi.90214.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cheng, L. Articles by Behar, J. Search for Related Content PubMed PubMed Citation Articles by Cheng, L. Articles by Behar, J.

NEUROREGULATION AND MOTILITY

Overexpression of progesterone receptor B increases sensitivity of human colon muscle cells to progesterone

Departments of Medicine and Surgery, Rhode Island Hospital and Warren Alpert Medical School, Brown University, Providence, Rhode Island

Submitted 27 February 2008 ; accepted in final form 1 July 2008

Colon muscle strips and cells from female patients with slow-transit constipation (STC) exhibit impaired motility, signal transduction abnormalities characterized by downregulation of G_q/11 and upregulation of G_s proteins, decreased cyclooxygenase (COX)-1 and thromboxane (Tx)B₂ levels, increased COX-2 and PGE₂ levels, and overexpression of progesterone receptors (PGR). Progesterone (P₄) treatment of normal cells reproduced these motility and signal transduction abnormalities. The purpose of the study was to examine whether overexpression of PGR-B reproduces these abnormalities by rendering the cells more sensitive to physiological concentrations of P₄. Cultured human colon muscle was transfected with a plasmid DNA expressing PGR-B. The mRNAs of PGR, COX-1, COX-2, and G_q/11 were determined by quantitative real-time PCR. Their protein expression was determined by Western blot, and prostaglandins were measured by radioimmunoassay. Cultured muscle cells maintained their phenotypic features determined with myosin light chain (MLC) and h-caldesmon antibodies. Control and transfected muscle cells responded to 10^–6 M P₄. In contrast, muscle cells transfected with PGR-B responded to lower P₄ concentration (10^–7 M). This P₄ concentration reduced MLC phosphorylation induced by CCK-8 (10^–8 M), downregulated G_q/11, and decreased COX-1 and TxB₂ levels. It upregulated G_s proteins. It also increased COX-2 and PGE₂ levels. We conclude that overexpression of PGR-B renders the cells more sensitive to physiological concentrations of P₄. These results are consistent with the hypothesis that overexpression of PGR-B contributes to the motility and signal transduction abnormalities observed in female patients with STC and normal serum levels of P₄.

G proteins; cyclooxygenase enzymes; prostaglandins