β2 and β4 Subunits of BK Channels Confer Differential Sensitivity to Acute Modulation by Steroid Hormones

King, Jonathan T.; Lovell, Peter V.; Rishniw, Mark; Kotlikoff, Michael I.; Zeeman, Mary Lou; McCobb, David P.

doi:10.1152/jn.01352.2005

Cited by 73 publications

(76 citation statements)

References 56 publications

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“…This could explain the high sensitivity of BK channels to tamoxifen, as has already been reported for E 2 in a previous work (Coiret et al, 2005). In the same way, King et al (2006) reported that the nature of ␤ subunits that are coexpressed with ␣ subunit in human embryonic kidney 293 cells was able to influence the sensitivity of the BK channel to different kinds of steroids. Furthermore, such discrepancies have also been reported in cultured endothelial cells and SMC from human coronary arteries (Liu et al, 2003) and seem to be dependent on the cell type.…”

Section: Tamoxifen Bk Channels and Mcf-7 Cells 847supporting

confidence: 74%

The Antiestrogen Tamoxifen Activates BK Channels and Stimulates Proliferation of MCF-7 Breast Cancer Cells

Coiret

Borowiec²,

Mariot³

et al. 2006

Mol Pharmacol

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In the present study, we investigated the effect of the antiestrogen compound tamoxifen on BK channels by the use of the patch-clamp technique. The perfusion of 10 nM tamoxifen significantly increased the magnitude of a voltage-dependent K ϩ current by 22.6 Ϯ 10.6% (n ϭ 23). The effect of tamoxifen was always obtained in the first minute, peaked at 5.9 Ϯ 2.2 min (n ϭ 23), and was abolished by the perfusion of tetraethylammonium (0.5 mM), charybdotoxin (50 nM), or iberiotoxin (100 nM). The stimulatory effect of 10 nM tamoxifen was the same at low (50 nM) and high (700 nM) internal calcium concentration and was not additive to that of 17-␤-estradiol (E 2 ) or its membrane-impermeant form, ␤-estradiol 6-(O-carboxymethyl)-oxime:bovine serum albumin. Furthermore, the effect of tamoxifen was still recorded in the presence of the selective estrogen receptor antagonist faslodex (ICI-182,780; 1 M). At the singlechannel level, tamoxifen significantly increased the open probability of the BK channel by 46.2 Ϯ 10.1% (n ϭ 4) without changing its unitary conductance. Moreover, we show here that the stimulation of BK channel activity by tamoxifen is involved in MCF-7 cell proliferation. Taken together, these results permitted us to identify the BK channel as the molecular target of tamoxifen that probably acts at the same extracellular molecular level as E 2 . The site of action of tamoxifen is probably the channel itself or the auxiliary ␤ subunits.Breast cancer is generally believed to arise when dividing cells undergo mutations, and these genetically damaged cells become susceptible to unrestrained division. Thus, female hormones and other hormones that affect growth of the mammary gland are potential risk factors for breast cancer. In contrast, factors that induce differentiation in the mammary gland, such as pregnancy and lactation, are likely to reduce the risk of breast cancer. In the case of breast cancer, estrogens are still one of the most important risk factors. Indeed, whereas 17-␤-estradiol (E 2 ) is a key growth regulator in the normal mammary gland, clinical and experimental data have clearly established that exposure to this steroid hormone is also the leading cause of sporadic female breast cancer. Thus, the usefulness of antiestrogens and/or chemopreventives is closely associated with antagonizing the activity of E 2 . The fact that estrogens may affect carcinogenesis by acting either as initiators (i.e., directly damage DNA; Liehr and Ricci, 1996) or as promoters (i.e., promoting the growth and/or survival of initiated cells; ESHRE Capri Workshop, 2004;Veronesi et al., 2005) has justified the use of antiestrogenic compounds such as tamoxifen in estrogenic hormone replacement therapy. However, in addition to their key role in female reproductive functions, estrogens have beneficial effects on unrelated tissues, as demonstrated by the effects of hormone replacement therapy on postmenopausal women (Mitlack and Cohen, 1997;Cosman and Lindsay, 1999). Indeed, estrogens can prevent osteoporosis by inhibitin...

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Section: Tamoxifen Bk Channels and Mcf-7 Cells 847supporting

confidence: 74%

The Antiestrogen Tamoxifen Activates BK Channels and Stimulates Proliferation of MCF-7 Breast Cancer Cells

Coiret

Borowiec²,

Mariot³

et al. 2006

Mol Pharmacol

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“…Several steroids other than bile acids have been reported to increase BK NPo, including 17b-estradiol, xenoestrogens, androgens, and gluco-and mineralocorticoids. None of these steroids, however, appear to require the specific presence of b 1 subunits for activating the channel (5,44,45), as LC does (6). Compared with other lipids and steroids, bile acids distinctly possess a unique bean shape and physicochemical properties (18).…”

Section: Discussionmentioning

confidence: 99%

“…In vascular smooth muscle, this BK channelmediated negative feedback mechanism serves to control myogenic tone and favors relaxation (1,2). A wide variety of physiologically relevant steroids, including estrogens, androgens, mineralo-and glucocorticoids, and bile acids, increase BK channel activity (3)(4)(5), a mechanism that might contribute to nongenomic modulation of myogenic tone. In particular, lithocholate (LC) and other bile acids, at aqueous concentrations ranging from 10 to 300 mM, are highly effective activators of BK channels (4,6).…”

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confidence: 99%

Structural determinants of monohydroxylated bile acids to activate β1 subunit-containing BK channels

Bukiya

McMillan

Parrill

et al. 2008

Journal of Lipid Research

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Lithocholate (LC) (10-300 mM) in physiological solution is sensed by vascular myocyte large conductance, calcium-and voltage-gated potassium (BK) channel b 1 accessory subunits, leading to channel activation and arterial dilation. However, the structural features in steroid and target that determine LC action are unknown. We tested LC and close analogs on BK channel (pore-forming cbv11b 1 subunits) activity using the product of the number of functional ion channels in the membrane patch (N) and the open channel probability (Po). LC (5b-cholanic acid-3a-ol), 5a-cholanic acid-3a-ol, and 5b-cholanic acid-3b-ol increased NPo (EC 50 ?45 mM). At maximal increase in NPo, LC increased NPo by 180%, whereas 5a-cholanic acid-3a-ol and 5b-cholanic acid-3b-ol raised NPo by 40%. Thus, the a-hydroxyl and the cis A-B ring junction are both required for robust channel potentiation. Lacking both features, 5a-cholanic acid-3b-ol and 5-cholenic acid-3b-ol were inactive. Three-dimensional structures show that only LC displays a bean shape with clear-cut convex and concave hemispheres; 5a-cholanic acid-3a-ol and 5b-cholanic acid-3b-ol partially matched LC shape, and 5a-cholanic acid-3b-ol and 5-cholenic acid-3b-ol did not. Increasing polarity in steroid rings (5b-cholanic acid-3a-sulfate) or reducing polarity in lateral chain (5b-cholanic acid 3a-ol methyl ester) rendered poorly active compounds, consistent with steroid insertion between b 1 and bilayer lipids, with the steroid-charged tail near the aqueous phase. Molecular dynamics identified two regions in b 1 transmembrane domain 2 that meet unique requirements for bonding with the LC concave hemisphere, where the steroid functional groups are located.

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“…The chemotherapeutic xenoestrogen tamoxifen also increased the BK Ca probability of opening only in the BK Ca ␤1-subunit presence (40). Cells expressing BK Ca ␣␤4 channels confer particular sensitivity to the adrenal glucocorticoids cortisol and corticosterone and are potentiated to a lesser degree by other sex and stress steroids (41). Fatty acids such as arachidonic acid (AA) alter BK Ca ␤-subunit modulation of BK Ca channel inactivation.…”

Section: Bk Ca ␤-Subunit Pharmacologymentioning

confidence: 99%

A Marriage of Convenience: β-Subunits and Voltage-dependent K+ Channels

Torres

Morera

Carvacho

et al. 2007

Journal of Biological Chemistry

107

103

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The movement of ions across cell membranes is essential for a wide variety of fundamental physiological processes, including secretion, muscle contraction, and neuronal excitation. This movement is possible because of the presence in the cell membrane of a class of integral membrane proteins dubbed ion channels. Ion channels, thanks to the presence of aqueous pores in their structure, catalyze the passage of ions across the otherwise ion-impermeable lipid bilayer. Ion conduction across ion channels is highly regulated, and in the case of voltage-dependent K

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β2 and β4 Subunits of BK Channels Confer Differential Sensitivity to Acute Modulation by Steroid Hormones

Cited by 73 publications

References 56 publications

The Antiestrogen Tamoxifen Activates BK Channels and Stimulates Proliferation of MCF-7 Breast Cancer Cells

The Antiestrogen Tamoxifen Activates BK Channels and Stimulates Proliferation of MCF-7 Breast Cancer Cells

Structural determinants of monohydroxylated bile acids to activate β1 subunit-containing BK channels

A Marriage of Convenience: β-Subunits and Voltage-dependent K+ Channels

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