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Modulation of mitochondrial Ca 2+ uptake by estrogen receptor agonists and antagonists

Modulation of mitochondrial Ca 2+ uptake by estrogen receptor agonists and antagonists 1 Ca2+ uptake by mitochondria is a key element in the control of cellular Ca2+ homeostasis and Ca2+‐dependent phenomena. It has been known for many years that this Ca2+ uptake is mediated by the mitochondrial Ca2+ uniporter, a specific Ca2+ channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter. 2 The specific α‐ER agonist 4,4′,4″‐(4‐propyl‐(1H)‐pyrazole‐1,3,5‐triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca2+ uptake in permeabilized HeLa cells by 10‐fold at 2 μM. Consistently, PPT largely increased the histamine‐induced mitochondrial (Ca2+) peak and reduced the cytosolic one. 3 Diethylstilbestrol and 17‐β‐estradiol (but not 17‐α‐estradiol) were active at pharmacological concentrations while the β‐estrogen‐receptor agonist 2,3‐bis(4‐hydroxyphenyl)‐propionitrile (DPN) was little effective. 4 The ER modulators tamoxifen and 4‐hydroxy‐tamoxifen inhibited mitochondrial Ca2+ uptake (IC50 2.5±1.5 and 2.5±1.4 μM, mean±s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect. 5 Activation by PPT was immediate and inhibition by tamoxifen or 4‐hydroxy‐tamoxifen required only 5 min to reach maximum. 6 Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca2+ uptake. 7 These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca2+ uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported effects of these compounds. British Journal of Pharmacology (2005) 145, 862–871. doi:10.1038/sj.bjp.0706265 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Modulation of mitochondrial Ca 2+ uptake by estrogen receptor agonists and antagonists

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References (65)

Publisher
Wiley
Copyright
2005 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0706265
pmid
15912132
Publisher site
See Article on Publisher Site

Abstract

1 Ca2+ uptake by mitochondria is a key element in the control of cellular Ca2+ homeostasis and Ca2+‐dependent phenomena. It has been known for many years that this Ca2+ uptake is mediated by the mitochondrial Ca2+ uniporter, a specific Ca2+ channel of the inner mitochondrial membrane. We have shown previously that this channel is strongly activated by a series of natural phytoestrogenic flavonoids. We show here that several agonists and antagonists of estrogen receptors (ERs) also modulate the activity of the uniporter. 2 The specific α‐ER agonist 4,4′,4″‐(4‐propyl‐(1H)‐pyrazole‐1,3,5‐triyl)trisphenol (PPT) was the strongest activator, increasing the rate of mitochondrial Ca2+ uptake in permeabilized HeLa cells by 10‐fold at 2 μM. Consistently, PPT largely increased the histamine‐induced mitochondrial (Ca2+) peak and reduced the cytosolic one. 3 Diethylstilbestrol and 17‐β‐estradiol (but not 17‐α‐estradiol) were active at pharmacological concentrations while the β‐estrogen‐receptor agonist 2,3‐bis(4‐hydroxyphenyl)‐propionitrile (DPN) was little effective. 4 The ER modulators tamoxifen and 4‐hydroxy‐tamoxifen inhibited mitochondrial Ca2+ uptake (IC50 2.5±1.5 and 2.5±1.4 μM, mean±s.d., respectively) both in the presence and in the absence of PPT, but raloxifene and the pure estrogen antagonist ICI 182,780 produced no effect. 5 Activation by PPT was immediate and inhibition by tamoxifen or 4‐hydroxy‐tamoxifen required only 5 min to reach maximum. 6 Tamoxifen did not modify mitochondrial membrane potential and PPT induced a slow mitochondrial depolarization at higher concentrations than those required to activate mitochondrial Ca2+ uptake. 7 These results suggest that some kind of ER or related protein located in mitochondria controls the activity of the Ca2+ uniporter by a nongenomic mechanism. This novel mechanism of action of estrogen agonists and antagonists can provide a new interpretation for several previously reported effects of these compounds. British Journal of Pharmacology (2005) 145, 862–871. doi:10.1038/sj.bjp.0706265

Journal

British Journal of PharmacologyWiley

Published: Aug 1, 2005

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