Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells

Tajima, Nobuyoshi; Itokazu, Yutaka; Korpi, Esa R.; Somerharju, Pentti; Käkelä, Reijo

doi:10.1074/jbc.m110.149898

Cited by 44 publications

(35 citation statements)

References 70 publications

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“…2C). This result differs from findings obtained for BK channels in glioma cells [25] but is consistent with previously published bilayer data [6], as well as data obtained in IGR 39 cells [45]. The time course of current rise is gradual, with maximal current observed at about 10 minutes after the application of MβCD (Fig.…”

Section: Resultssupporting

confidence: 90%

Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

et al. 2011

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In the search to uncover ethanol's molecular mechanisms, the calcium and voltage activated, large conductance potassium channel (BK) has emerged as an important molecule. We examine how cholesterol content in bilayers of 1,2-dioleoyl-3-phosphatidylethanolamine (DOPE)/sphingomyelin (SPM) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylserine (POPS) affect the function and ethanol sensitivity of BK. In addition, we examine how manipulation of cholesterol in biological membranes modulates ethanol's actions on BK. We report that cholesterol levels regulate the change in BK channel open probability elicited by 50 mM ethanol. Low levels of cholesterol (<20%, molar ratio) supports ethanol activation, while high levels of cholesterol leads to ethanol inhibition of BK. To determine if cholesterol affects BK and its sensitivity to ethanol through a direct cholesterol-protein interaction or via an indirect action on the lipid bilayer, we used the synthetic enantiomer of cholesterol (ent-CHS). We found that 20% and 40% ent-CHS had little effect on the ethanol sensitivity of BK, when compared with the same concentration of nat-CHS. We accessed the effects of ent-CHS and nat-CHS on the molecular organization of DOPE/SPM monolayers at the air/water interface. The isotherm data showed that ent-CHS condensed DOPE/SPM monolayer equivalently to nat-CHS at a 20% concentration, but slightly less at a 40% concentration. Atomic force microscopy (AFM) images of DOPE/SPM membranes in the presence of ent-CHS or nat-CHS prepared with LB technique or vesicle deposition showed no significant difference in topographies, supporting the interpretation that the differences in actions of nat-CHS and ent-CHS on BK channel are not likely from a generalized action on bilayers. We conclude that membrane cholesterol influences ethanol's modulation of BK in a complex manner, including an interaction with the channel protein. Finally, our results suggest that an understanding of membrane protein function and modulation is impossible unless protein and surrounding lipid are considered as a functional unit.

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Section: Resultssupporting

confidence: 90%

Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

et al. 2011

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“…By this way, TMS would disrupt the feedback loop that links Ab 1-42 accumulation and BK channel suppression, thereby mitigating synaptic dysfunction and cell death. Such beneficial effects of BK channel facilitation are consistent with the general recognition that BK channel activity supports cell survival and proliferation of various neural and non-neural cells (Liu et al,1999;Hu et al, 2001;Williams et al, 2004;Lu et al, 2006;Yu et al, 2010;Tajima et al, 2011). In our previous experiments, Ab-induced suppression of BK channels increased cortical excitability , which is consistent with clinical evidence that cortical excitability is elevated in AD patients (Perretti et al, 1996;Ferreri et al, 2003;Inghilleri et al, 2006).…”

Section: Discussionsupporting

confidence: 87%

Improvement of spatial learning by facilitating large-conductance calcium-activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice

et al. 2015

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“…Furthermore, we found higher estimates of absolute cholesterol concentrations in the melanoma compared with controls. Increased cholesterol concentrations are associated with proliferating cells and metastases of melanoma as previously stated [36,44]. Since the transfer of long chain fatty acid into mitochondria is the rate determining step in β-oxidation [45,46,47], the enzymes responsible for transfer and β-oxidation of fatty acids (like CPT-1) could be the targets of antitumor drugs [48,49,50,51].…”

Section: Discussionmentioning

confidence: 99%

Studies of Secondary Melanoma on C57BL/6J Mouse Liver Using 1H NMR Metabolomics

et al. 2013

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NMR metabolomics, consisting of solid state high resolution magic angle spinning (HR-MAS) 1H-NMR, liquid state high resolution 1H-NMR, and principal components analysis (PCA) has been used to study secondary metastatic B16-F10 melanoma in C57BL/6J mouse liver. The melanoma group can be differentiated from its control group by PCA analysis of the estimates of absolute concentrations from liquid state 1H-NMR spectra on liver tissue extracts or by the estimates of absolute peak intensities of metabolites from 1H HR-MAS-NMR data on intact liver tissues. In particular, we found that the estimates of absolute concentrations of glutamate, creatine, fumarate and cholesterol are elevated in the melanoma group as compared to controls, while the estimates of absolute concentrations of succinate, glycine, glucose, and the family of linear lipids including long chain fatty acids, total choline and acyl glycerol are decreased. The ratio of glycerophosphocholine (GPC) to phosphocholine (PCho) is increased by about 1.5 fold in the melanoma group, while the estimate of absolute concentration of total choline is actually lower in melanoma mice. These results suggest the following picture in secondary melanoma metastasis: Linear lipid levels are decreased by beta oxidation in the melanoma group, which contributes to an increase in the synthesis of cholesterol, and also provides an energy source input for TCA cycle. These findings suggest a link between lipid oxidation, the TCA cycle and the hypoxia-inducible factors (HIF) signal pathway in tumor metastases. Thus, this study indicates that the metabolic profile derived from NMR analysis can provide a valuable bio-signature of malignancy and cell hypoxia in metastatic melanoma.

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Activity of BKCa Channel Is Modulated by Membrane Cholesterol Content and Association with Na+/K+-ATPase in Human Melanoma IGR39 Cells

Abstract: Interaction of large conductance

Cited by 44 publications

References 70 publications

Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

Cholesterol Tuning of BK Ethanol Response Is Enantioselective, and Is a Function of Accompanying Lipids

Improvement of spatial learning by facilitating large-conductance calcium-activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice

Studies of Secondary Melanoma on C57BL/6J Mouse Liver Using 1H NMR Metabolomics

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