Effect of estrogen upon cyclic ADP ribose metabolism: beta-estradiol stimulates ADP ribosyl cyclase in rat uterus.
Cyclic ADP ribose (cADPR) has been shown to trigger Ca2+ release from intracellular stores through ryanodine receptor/channel. In our previous study we observed that all-trans-retinoic acid stimulates cADPR synthesis by ADP ribose cyclase (ADPR cyclase) in cultured epithelial cells. We have now investigated whether cADPR may play a signaling role in action of beta-estradiol (E2), an archetypal steroid superfamily hormone, upon its major target organ, uterus, in vivo. Administration of E2 to gonadectomized rats (0.2 mg/kg per day for 7 days) resulted in an approximately Delta + 300% increase of ADPR cyclase activity in extracts from uterus, but in liver, brain, or skeletal muscle ADPR cyclase was unchanged. Most of the E2-stimulated uterine ADPR cyclase was associated with membranes. The higher ADPR cyclase activity in response to E2 was due to the increase of VMAX without change in Km. Simultaneous administration of estrogen antagonist tamoxifen (8 mg/kg per day) with E2 (0.2 mg/kg per day) prevented an increase in ADPR cyclase. In uterine extracts from E2-treated rats, the rate of cADPR inactivation by cADPR hydrolase and the activity of NADase was increased, but to a much lesser degree than activity of ADPR cyclase. Our results indicate that E2, via action to its nuclear receptors in vivo, increases ADPR cyclase activity in uterus. We propose that some of the estrogen effects, and by extension the effects of other steroid superfamily hormones, upon specialized cellular functions and upon hormone-induced gene expression in target cells, are mediated by cADPR-Ca2+ release pathway.
Chini
E N
EN
Renal Pathophysiology Laboratory, Department of Physiology and Biophysics, Mayo Clinic and Mayo Medical School, Rochester, MN 55905, USA.
de Toledo
F G
FG
Thompson
M A
MA
Dousa
T P
TP
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D001921:Brain / Q000201:enzymology; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D036563:Cyclic ADP-Ribose; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009130:Muscle, Smooth / Q000201:enzymology; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000378:metabolism; D010052:Ovariectomy; D010063:Ovum / Q000502:physiology; D016105:Parathyroidectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011959:Receptors, Estradiol / Q000502:physiology; D012617:Sea Urchins; D015290:Second Messenger Systems; D013629:Tamoxifen / Q000494:pharmacology; D013965:Thyroidectomy; D014599:Uterus / Q000201:enzymology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D011959:Receptors, Estradiol; D013629:Tamoxifen; D009243:NAD; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D004958:Estradiol; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498156:Cd38 protein, rat; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium