Non-genomic effects of tamoxifen on the activation of membrane-bound guanylate cyclase GC-A.
Oestrogen is known to exert both genomic and non-genomic effects on target tissues. Unlike the genomic effects, the identity of receptors mediating the non-genomic effects of oestrogen remains controversial. 17beta-estradiol has been shown to activate membrane-bound guanylate cyclase GC-A in PC12 cells in a non-genomic manner. To examine whether 17beta-estradiol exerts a similar effect in other cell types, we measured the effect of 17beta-estradiol and tamoxifen, an anti-oestrogen, on guanylate cyclase activity in porcine kidney proximal tubular LLC-PK1 cells. 17beta-estradiol increased cGMP levels in LLC-PK1 cells. Interestingly, addition of tamoxifen also increased cGMP levels in a concentration-dependent manner in LLC-PK1 cells. The effects of both 17beta-estradiol and tamoxifen on guanylate cyclase activity were not additive, suggesting that oestrogen and tamoxifen activate the same enzyme. Similar phenomena were also observed in LLC-PK1 cell membrane preparation. LLC-PK1 cells do not express membrane-bound guanylate cyclase GC-B and express low levels of membrane-bound guanylate cyclase GC-C. Tamoxifen inhibited the activation of GC-A by atrial natriuretic factor (ANF). However, it did not affect membrane-bound guanylate cyclase GC-C stimulated by guanylin or Escherichia coli heat-stable toxin STa. These results indicate that 17beta-estradiol and tamoxifen activate GC-A in LLC-PK1 cells. Thus, tamoxifen functions as an agonist rather than an antagonist for the membrane oestrogen receptor coupled to the activation of GC-A.
Chen
Zi-Jiang
ZJ
Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Vetter
Michael
M
Chang
Geen-Dong
GD
Liu
Shiguo
S
Ding
Yaxian
Y
Chang
Chung-Ho
CH
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005768:Gastrointestinal Hormones / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D045265:Natriuretic Peptides; D010455:Peptides / Q000494:pharmacology; D013552:Swine; D013629:Tamoxifen / Q000494:pharmacology*
D004965:Estrogen Antagonists; D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; D013629:Tamoxifen; C072685:guanylin; D004958:Estradiol; D006162:Guanylate Cyclase; D006152:Cyclic GMP