The activation by estrogen receptor agonists of the BK(Ca)-channel in human cardiac fibroblasts.
The agonists selective for estrogen receptor (ER)-alpha (4,4',4''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl) tris-phenol, PPT) and ER-beta (2,3-bis(4-hydroxyphenyl)-propionitrile, DPN) are known to stimulate ER-alpha and ER-beta receptors, respectively. It remains unknown whether these two agents regulate the activity of ion channels via a direct stimulation. In this study, we tested the hypothesis that DPN or PPT stimulates the large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in cultured human cardiac fibroblasts (HCFs). In whole-cell configuration, depolarizing pulses evoked K(+) outward currents in an outward rectification in HCFs, the amplitude of which was increased in the presence of DPN or PPT. In inside-out patches, the activity of BK(Ca)-channel with a conductance of 167+/-8 pS was observed in these cells. PPT or DPN applied to the intracellular face of the membrane enhanced the activity of BK(Ca) channels with no change in single-channel conductance. DPN and PPT increased BK(Ca)-channel activity with an EC(50) value of 2.3 and 2.6 microM, respectively. The mean closed time of these channels during the exposure to these compounds was reduced with no change in the gating charge of the channels. Intracellular Ca(2+) was not altered by these two compounds. RT-PCR analysis revealed that no change in the transcriptional level of the BK(Ca)-channel alpha-subunit was observed in chronic treatment with these two compounds. PPT- and DPN-stimulated increase in BK(Ca) channels reveal novel pharmacological properties attributable to the activity of these channels, and their increase in BK(Ca) channels activity in HCFs may contribute to cell function.
Wang
Ya-Jean
YJ
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Lin
Ming-Wei
MW
Wu
Sheng-Nan
SN
Sung
Ruey J
RJ
D002118:Calcium / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D045166:Estradiol Congeners / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D000077267:Fulvestrant; D006321:Heart; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D009570:Nitriles / Q000494:pharmacology*; D012333:RNA, Messenger; D011960:Receptors, Estrogen / Q000819:agonists*; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology; D013997:Time Factors; D011422:Propionates
D002118:Calcium; D004958:Estradiol; D045166:Estradiol Congeners; D000077267:Fulvestrant; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009570:Nitriles; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000077185:Resveratrol; D013267:Stilbenes; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates