CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING |
Proapoptotic Triterpene electrophiles (avicins) form channels in membranes: cholesterol dependence
Xiaoxian Li 1, Bridgette Davis 1, Valsala Haridas 2, Jordan U Gutterman 2 and Marco Colombini 3*
1 U. Maryland
2 University of Texas
3 Univ. of Maryland
* To whom correspondence should be addressed. E-mail: colombin{at}umd.edu.
Submitted on July 13, 2004
Revised on August 11, 2004
Accepted on 5 January 2005
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Abstract |
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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 1.1nm. 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 non-selective but negatively-charged lipids confer cation selectivity (5:1,K+:Cl-) indicating that phospholipids form part of the 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.
Key Words:
apoptosis, erythrocytes, lipid dependence, planar membranes, pore, self-assembly
