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Titolo:
Tamoxifen activates smooth muscle BK channels through the regulatory beta 1 subunit
Autore:
Dick, GM; Rossow, CF; Smirnov, S; Horowitz, B; Sanders, KM;
Indirizzi:
Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA Univ Nevada Reno NV USA 89557 ept Physiol & Cell Biol, Reno, NV 89557 USA Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England Univ Bath Bath Avon England BA2 7AY harmacol, Bath BA2 7AY, Avon, England
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 37, volume: 276, anno: 2001,
pagine: 34594 - 34599
SICI:
0021-9258(20010914)276:37<34594:TASMBC>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
CANINE COLONIC MYOCYTES; RAT CEREBRAL-ARTERIES; HIGH-DOSE TAMOXIFEN; PHASE-I TRIAL; NONGENOMIC ACTIONS; POTASSIUM CHANNEL; K-CHANNELS; INHIBITION; CA2+; COMBINATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Dick, GM Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA Univ Nevada Reno NV USA 89557 ol & Cell Biol, Reno, NV 89557 USA
Citazione:
G.M. Dick et al., "Tamoxifen activates smooth muscle BK channels through the regulatory beta 1 subunit", J BIOL CHEM, 276(37), 2001, pp. 34594-34599

Abstract

Estrogen (17 beta -estradiol; 17 betaE) and xenoestrogens, estrogenic compounds that are not steroid hormones, have nongenomic actions at plasma membrane receptors unrelated to the nuclear estrogen receptor. The open probability (P-o) of large conductance Ca2+/voltage-sensitive k(+)(BK) channels isincreased by 17 betaE through the regulatory beta1 subunit. The pharmacological nature of the putative membrane binding site is unclear. We probed the site by determining whether tamoxifen ((Z)-1-(p-dimethylaminoethoxy-phenyl)-1,2-diphenyl-1-butene; Tx), a chemotherapeutic xenoestrogen, increased P-o in clinically relevant concentrations (0.1-10 muM). In whole cell patch clamp recordings on canine colonic myocytes, which express the beta1 subunit, Tx activated charybdotoxin-sensitive K+ current. In single channel experiments, Tx increased the NPo (P-o x number channel; N) and decreased the unitary conductance (gamma) of BK channels. Tx increased NPo (EC50 = 0.65 muM) in excised membrane patches independent of Ca2+ changes. The Tx mechanismof action requires the beta1 subunit, as Tx increased the NPo of Slo alphaexpressed in human embryonic kidney cells only in the presence of the beta1 subunit. Tx decreased gamma of the alpha subunit expressed alone, withouteffect on NTPo. Our data indicate that Tx increases BK channel activity intherapeutic concentrations and reveal novel pharmacological properties attributable to the a and beta1 subunits. These data shed light on BK channel structure and function, non-genomic mechanisms of regulation, and physiologically and therapeutically relevant effects of xenoestrogens.

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Documento generato il 04/12/20 alle ore 19:33:37