Structural specificity of the NaK-ATPase inhibition by sanguinarine, an isoquinoline benzophenanthridine alkaloid

Cohen, H.; Seifen, Ernst; Straub, K. D.; Tiefenback, Claudia; Stermitz, Frank R.

doi:10.1016/0006-2952(78)90325-8

Cited by 40 publications

(17 citation statements)

References 17 publications

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“…1) and nucleophilic aminothiols in rat liver L-alanine amino-transferase [65] and guinea pig brain NKA [66]. However, no detailed molecular data are available as to where these thiols are on NKA, and as shown in our sequence alignments, cysteines are absent from the discovered motifs.…”

Section: Discussionmentioning

confidence: 99%

Canonical Bcl-2 Motifs of the Na+/K+ Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Lauf

Heiny

Meller

et al. 2013

Cell Physiol Biochem

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Background/Aims: Chelerythrine [CET], a protein kinase C [PKC] inhibitor, is a prop-apoptotic BH3-mimetic binding to BH1-like motifs of Bcl-2 proteins. CET action was examined on PKC phosphorylation-dependent membrane transporters (Na⁺/K⁺ pump/ATPase [NKP, NKA], Na⁺-K⁺-2Cl⁺ [NKCC] and K⁺-Cl^- [KCC] cotransporters, and channel-supported K⁺ loss) in human lens epithelial cells [LECs]. Methods: K⁺ loss and K⁺ uptake, using Rb⁺ as congener, were measured by atomic absorption/emission spectrophotometry with NKP and NKCC inhibitors, and Cl^- replacement by NO₃^ˉ to determine KCC. ³H-Ouabain binding was performed on a pig renal NKA in the presence and absence of CET. Bcl-2 protein and NKA sequences were aligned and motifs identified and mapped using PROSITE in conjunction with BLAST alignments and analysis of conservation and structural similarity based on prediction of secondary and crystal structures. Results: CET inhibited NKP and NKCC by >90% (IC₅₀ values ∼35 and ∼15 µM, respectively) without significant KCC activity change, and stimulated K⁺ loss by ∼35% at 10-30 µM. Neither ATP levels nor phosphorylation of the NKA α1 subunit changed. ³H-ouabain was displaced from pig renal NKA only at 100 fold higher CET concentrations than the ligand. Sequence alignments of NKA with BH1- and BH3-like motifs containing pro-survival Bcl-2 and BclXl proteins showed more than one BH1-like motif within NKA for interaction with CET or with BH3 motifs. One NKA BH1-like motif (ARAAEILARDGPN) was also found in all P-type ATPases. Also, NKA possessed a second motif similar to that near the BH3 region of Bcl-2. Conclusion: Findings support the hypothesis that CET inhibits NKP by binding to BH1-like motifs and disrupting the α₁ subunit catalytic activity through conformational changes. By interacting with Bcl-2 proteins through their complementary BH1- or BH3-like-motifs, NKP proteins may be sensors of normal and pathological cell functions, becoming important yet unrecognized signal transducers in the initial phases of apoptosis. CET action on NKCC1 and K⁺ channels may involve PKC-regulated mechanisms; however, limited sequence homologies to BH1-like motifs cannot exclude direct effects.

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Section: Discussionmentioning

confidence: 99%

Canonical Bcl-2 Motifs of the Na+/K+ Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Lauf

Heiny

Meller

et al. 2013

Cell Physiol Biochem

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“…Cardiac glycosides enhance cardiac contractility by inhibiting Na + -Ca 2+ exchanger via suppression of Na + -K + -ATPase (11). However, the positive inotropic effect of berberine is unlikely to be due to inhibition of Na + -K + -ATPase, since berberine, at 100 ìM, had no effect on the activity of guinea pig brain Na + -K + -ATPase (10). Berberine inhibited cardiac phosphodiesterase with an IC 50 value of 692 ìM (10).…”

Section: Pharmacology Inotropic Effectmentioning

confidence: 99%

Cardiovascular Actions of Berberine

Lau

Yao

Chen

et al. 2001

Cardiovascular Drug Reviews

238

126

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Berberine, is an alkaloid from Hydrastis canadensis L., Chinese herb Huanglian, and many other plants. It is widely used in traditional Chinese medicine as an antimicrobial in the treatment of dysentery and infectious diarrhea. This manuscript describes cardiovascular effects of berberine and its derivatives, tetrahydroberberine and 8-oxoberberine. Berberine has positive inotropic, negative chronotropic, antiarrhythmic, and vasodilator properties. Both derivatives of berberine have antiarrhythmic activity. Some of cardiovascular effects of berberine and its derivatives are attributed to the blockade of K + channels (delayed rectifier and K ATP ) and stimulation of Na + -Ca 2+ exchanger. Berberine has been shown to prolong the duration of ventricular action potential. Its vasodilator activity has been attributed to multiple cellular mechanisms. The cardiovascular effects of berberine suggest its possible clinical usefulness in the treatment of arrhythmias and/or heart failure.

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“…The CET structure-related sanguinarines have been known for a long time to inhibit the NKP in a variety of tissue preparations [11,12,13,14,15,16,17], without an explanation for this effect. Sequence homologies between BH1-like motifs originally reported to bind CET in Bcl-Xl proteins and found in the cytoplasmic aspect of the crystal structure of the NKP led to the hypothesis that CET may inhibit the NKP function through these BH1 motifs [10].…”

Section: Introductionmentioning

confidence: 99%

Surface-Enhanced Raman Spectroscopy (SERS) Tracking of Chelerythrine, a Na⁺/K⁺Pump Inhibitor, into Cytosol and Plasma Membrane Fractions of Human Lens Epithelial Cell Cultures

Dorney

Sizemore

Alqahtani

et al. 2013

Cell Physiol Biochem

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Background/Aims: The quaternary benzo-phenanthridine alkaloid (QBA) chelerythrine (CET) is a pro-apoptotic drug and Na⁺/K⁺ pump (NKP) inhibitor in human lens epithelial cells (HLECs). In order to obtain further insight into the mechanism of NKP inhibition by CET, its sub-cellular distribution was quantified in cytosolic and membrane fractions of HLEC cultures by surface-enhanced Raman spectroscopy (SERS). Methods: Silver nanoparticles (AgNPs) prepared by the Creighton method were concentrated, and size-selected using a one-step tangential flow filtration approach. HLECs cultures were exposed to 50 μM CET in 300 mOsM phosphate-buffered NaCl for 30 min. A variety of cytosolic extracts, crude and purified membranes, prepared in lysing solutions in the presence and absence of a non-ionic detergent, were incubated with AgNPs and subjected to SERS analysis. Determinations of CET were based on a linear calibration plot of the integrated CET SERS intensity at its 659 cm^-1 marker band as a function of CET concentration. Results: SERS detected chemically unaltered CET in both cytosol and plasma membrane fractions. Normalized for protein, the CET content was some 100 fold higher in the crude and purified plasma membrane fraction than in the soluble cytosolic extract. The total free CET concentration in the cytosol, free of membranes or containing detergent-solubilized membrane material, approached that of the incubation medium of HLECs. Conclusion: Given a negative membrane potential of HLECs the data suggest, but do not prove, that CET may traverse the plasma membrane as a positively charged monomer (CET⁺) accumulating near or above passive equilibrium distribution. These findings may contribute to a recently proposed hypothesis that CET binds to and inhibits the NKP through its cytosolic aspect.

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Structural specificity of the NaK-ATPase inhibition by sanguinarine, an isoquinoline benzophenanthridine alkaloid

Cited by 40 publications

References 17 publications

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Cardiovascular Actions of Berberine

Surface-Enhanced Raman Spectroscopy (SERS) Tracking of Chelerythrine, a Na⁺/K⁺Pump Inhibitor, into Cytosol and Plasma Membrane Fractions of Human Lens Epithelial Cell Cultures

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Structural specificity of the NaK-ATPase inhibition by sanguinarine, an isoquinoline benzophenanthridine alkaloid

Cited by 40 publications

References 17 publications

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Canonical Bcl-2 Motifs of the Na<sup>+</sup>/K<sup>+</sup> Pump Revealed by the BH3 Mimetic Chelerythrine: Early Signal Transducers of Apoptosis?

Cardiovascular Actions of Berberine

Surface-Enhanced Raman Spectroscopy (SERS) Tracking of Chelerythrine, a Na+/K+Pump Inhibitor, into Cytosol and Plasma Membrane Fractions of Human Lens Epithelial Cell Cultures

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Surface-Enhanced Raman Spectroscopy (SERS) Tracking of Chelerythrine, a Na⁺/K⁺Pump Inhibitor, into Cytosol and Plasma Membrane Fractions of Human Lens Epithelial Cell Cultures