17Beta-estradiol induces gastrointestinal motility disorder by decreasing CPI-17 phosphorylation via changes in rho-family G-protein Rnd expression in small intestine.
In the present study, we investigated the long-term effects of 17beta-estradiol on the motility of small intestine in in vitro organ culture and in vivo treatment studies. When rat ileal circular smooth muscle tissues were cultured with 17beta-estradiol (0.1 and 1 microM) for 5 days, carbachol-induced contraction was inhibited. In ileal tissue isolated from ovariectomized rat treated with 17beta-estradiol (200 microg/kg/day s.c. for 3 days), carbachol-induced contraction was also impaired. Both in vitro and in vivo, 17beta-estradiol treatment upregulated heat shock protein 27 (HSP27) expression, indicating the activation of estrogen receptor in the intestinal smooth muscle. 17beta-estradiol did not change protein expression levels of RhoA and RhoA-associated coiled coil-forming serine/threonine kinases (ROCKs); however, it upregulated Rnd2 and Rnd3, Rho-family G-proteins that counteract the functions of RhoA, both in vitro and in vivo. In organ culture, treatment of ileal tissue with 17beta-estradiol greatly suppressed the carbachol-induced increase in phosphorylation at Thr38 in CPI-17 without altering total CPI-17 protein expression. These results suggest that 17beta-estradiol upregulates Rnd expression to inhibit the RhoA-mediated Ca(2+) sensitization of contractile mechanisms, which are mediated by CPI-17 phosphorylation in ileal smooth muscle. This mechanism may contribute to the intestinal motility disorder occurring in gender-dependent bowel diseases.
Shimomura
Aya
A
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
Ohama
Takashi
T
Hori
Masatoshi
M
Ozaki
Hiroshi
H
D000818:Animals; D002217:Carbachol; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects*; D010052:Ovariectomy; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D046509:Tissue Culture Techniques
D009124:Muscle Proteins; D010750:Phosphoproteins; C491519:Ppp1r14a protein, rat; D004958:Estradiol; D002217:Carbachol; D019204:GTP-Binding Proteins