Amphiphile regulation of ion channel function by changes in the bilayer; springconstant

by Lundbaek, Jens A.; Koeppe II, R. Erdman; Andersen, Olaf S.

Many drugs are amphiphiles that, in addition to binding to a particular; targetprotein,adsorbtocellmembranelipidbilayersandalter; intrinsicbilayerphysicalproperties(e.g.,bilayerthickness,; monolayercurvature,andelasticmoduli).Suchchangescanmodulate; membraneproteinfunctionbyalteringtheenergeticcost(Delta; G(bilayer))ofbilayerdeformationsassociatedwithprotein; conformationalchangesthatinvolvetheprotein-bilayerinterface.But; amphiphileshavecomplexeffectsonthephysicalpropertiesoflipid; bilayers,meaningthatthenetchangeinDeltaG(bilayer)cannotbe; predictedfrommeasurementsofisolatedchangesinsuchproperties.; Thus,thebilayercontributiontothepromiscuousregulationof; membraneproteinsbydrugsandotheramphiphilesremainsunknown.To; overcomethisproblem,weusegramicidinA(gA)channelsasmolecular; forceprobestomeasuretheneteffectofamphiphiles,at; concentrationsoftenusedinbiologicalresearch,onthebilayer; elasticresponsetoachangeinthehydrophobiclengthofanembedded; protein.Theeffectsofstructurallydiverseamphiphilescanbe; describedbychangesinaphenomenologicalbilayerspringconstant; (H-B)thatsummarizesthebilayerelasticproperties,assensedbya; bilayer-spanningprotein.Amphiphile-inducedchangesinH-B,measured; usinggAchannelsofaparticularlength,quantitativelypredict; changesinlifetimeforchannelsofadifferentlength-aswellas; changesintheinactivationofvoltage-dependentsodiumchannelsin; livingcells.TheuseofgAchannelsasmolecularforceprobesprovides; atoolforquantitative,predictivestudiesofbilayer-mediated; regulationofmembraneproteinfunctionbyamphiphiles.

Journal
Proceedings of the National Academy of Sciences of the United States of America
Volume
107
Issue
35
Year
2010
Start Page
15427
ISBN/ISSN
1091-6490; 0027-8424
PMID
20713738
DOI
10.1073/pnas.1007455107