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Modulation of mitochondrial Ca2+ uptake by estrogen receptor agonists and antagonists

AutorLobatón, Carmen D.; Vay, Laura; Hernández-SanMiguel, Esther; Santo-Domingo, Jaime; Moreno, Alfredo; Montero, Mayte ; Álvarez, Javier
Palabras claveAequorin
Fecha de publicaciónago-2005
EditorNature Publishing Group
CitaciónBritish Journal of Pharmacology 145(7): 862–871 (2005)
ResumenCa2+ 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. 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. 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. 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. Activation by PPT was immediate and inhibition by tamoxifen or 4-hydroxy-tamoxifen required only 5 min to reach maximum. 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. 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.
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