Proapoptotic triterpene electrophiles (avicins) form channels in membranes: cholesterol dependence.

Publisher: Cell Press Country of Publication: United States NLM ID: 0370626 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0006-3495 (Print) Linking ISSN: 00063495 NLM ISO Abbreviation: Biophys J Subsets: MEDLINE

Publication: Cambridge, MA : Cell Press
Original Publication: New York, Published by Rockefeller University Press [etc.] for the Biophysical Society.

Apoptosis*; Cell Membrane/*metabolism ; Cholesterol/*chemistry ; Saponins/*chemistry; Acacia/metabolism ; Animals ; Cholesterol/metabolism ; Dose-Response Relationship, Drug ; Erythrocytes/metabolism ; Humans ; Hydrogen-Ion Concentration ; Hydrolysis ; Male ; Membrane Proteins/chemistry ; Mitochondria/metabolism ; Models, Chemical ; Models, Molecular ; Oxidation-Reduction ; Phosphatidylcholines ; Phospholipids/chemistry ; Phospholipids/metabolism ; Potassium/chemistry ; Rats ; Rats, Sprague-Dawley ; Water/chemistry

Avicins, a family of triterpenoid saponins from Acacia victoriae, can regulate the innate stress response in human cells. Their ability to induce apoptosis in transformed cells makes them potential anticancer agents. We report that avicins can form channels in membranes. The conductance reached a steady state after each addition, indicating a dynamic equilibrium between avicin in solution and in the membrane. The high power dependence (up to 10) of the membrane conductance on the avicin concentration indicates the formation of multimeric channels, consistent with the estimated pore radius of 1.1 nm. This radius is too small to allow protein flux across the mitochondrial outer membrane, a process known to initiate apoptosis. Channel formation is lost when avicin's amphipathic side chain is removed, implicating this as the channel-forming region. A small difference in this side chain results in strong cholesterol dependence of channel formation in avicin G that is not found in avicin D. In neutral membranes, avicin channels are nonselective, but negatively-charged lipids confer cation selectivity (5:1, K(+):Cl(-)), indicating that phospholipids form part of the permeation pathway. Avicin channels in the mitochondrial outer membrane may favor apoptosis by altering the potential across this membrane and the intermembrane space pH.

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0 (Membrane Proteins)
0 (Phosphatidylcholines)
0 (Phospholipids)
0 (Saponins)
0 (avicin G)
059QF0KO0R (Water)
69279-91-0 (asolectin)
69451KN1RO (avicin D)
97C5T2UQ7J (Cholesterol)
RWP5GA015D (Potassium)

Date Created: 20050118 Date Completed: 20050817 Latest Revision: 20181113

20240628

PMC1305354

10.1529/biophysj.104.049403

15653745