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The Importance of Hydrophobic Coupling. Effects of Micelle-forming Amphiphiles and Cholesterol
2 Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
3 Institute of Biological Psychiatry, St. Hans Hospital, DK-4000 Roskilde, Denmark
4 Quantum Protein Center, The Technical University of Denmark, DK-2800, Lyngby, Denmark
5 Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701
Address correspondence to Jens A. Lundbæk, Institute of Biological Psychiatry, St. Hans Hospital, Boserupvej 2, DK-4000 Roskilde, Denmark. Fax: (45) 46 33 43 67. email: lundbaek{at}dadlnet.dk
Membrane proteins are regulated by the lipid bilayer composition. Specific lipid–protein interactions rarely are involved, which suggests that the regulation is due to changes in some general bilayer property (or properties). The hydrophobic coupling between a membrane-spanning protein and the surrounding bilayer means that protein conformational changes may be associated with a reversible, local bilayer deformation. Lipid bilayers are elastic bodies, and the energetic cost of the bilayer deformation contributes to the total energetic cost of the protein conformational change. The energetics and kinetics of the protein conformational changes therefore will be regulated by the bilayer elasticity, which is determined by the lipid composition. This hydrophobic coupling mechanism has been studied extensively in gramicidin channels, where the channel–bilayer hydrophobic interactions link a "conformational" change (the monomer
dimer transition) to an elastic bilayer deformation. Gramicidin channels thus are regulated by the lipid bilayer elastic properties (thickness, monolayer equilibrium curvature, and compression and bending moduli). To investigate whether this hydrophobic coupling mechanism could be a general mechanism regulating membrane protein function, we examined whether voltage-dependent skeletal-muscle sodium channels, expressed in HEK293 cells, are regulated by bilayer elasticity, as monitored using gramicidin A (gA) channels. Nonphysiological amphiphiles (ß-octyl-glucoside, Genapol X-100, Triton X-100, and reduced Triton X-100) that make lipid bilayers less "stiff", as measured using gA channels, shift the voltage dependence of sodium channel inactivation toward more hyperpolarized potentials. At low amphiphile concentration, the magnitude of the shift is linearly correlated to the change in gA channel lifetime. Cholesterol-depletion, which also reduces bilayer stiffness, causes a similar shift in sodium channel inactivation. These results provide strong support for the notion that bilayer–protein hydrophobic coupling allows the bilayer elastic properties to regulate membrane protein function.
Key Words: gramicidin A • bilayer material properties • bilayer deformation energy • hydrophobic coupling • lipid–protein interactions
Abbreviations used in this paper: ßOG, ß-octyl-glucoside; CMC, critical micellar concentration; DHA, docosahexaenoic acid; DOPC, dioleoylphosphatidylcholine; gA, gramicidin A; GX100, Genapol X-100; HH, Hodgkin-Huxley; MßCD, methylated ß-cyclodextrin; TX100, Triton X-100; rTX100, reduced TX100.
1 Though
Gdef0 is determined by Ka, Kc, c0, d0, and r0, the precise value will be a function also of the constraints on lipid packing around the protein (Helfrich and Jakobsson, 1990; Nielsen and Andersen, 2000), as well as any spatial variation in the elastic moduli adjacent to the protein (Partenskii and Jordan, 2002). Further, although monolayer compression and bending are independent modes of deformation; the elastic moduli associated with these two modes of deformation are related by Kc=Ka·
(Evans and Skalak, 1979), where b 
24 (see Rawicz et al., 2000).
2 The CMC varies as a function of salt concentration (Walter et al., 2000). The quoted values are for 0.1–0.2 M NaCl solutions.
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