Abstract
Transmembrane segments of ion channels tend to match the hydrophobic thickness of lipid bilayers to minimize mismatch energy and to maintain their proper organization and function. To probe how ion channels respond to mismatch with lipid bilayers of different thicknesses, we examined the single channel activities of BK(Ca) (hSlo alpha-subunit) channels in planar bilayers of binary mixtures of DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) with phosphatidylcholines (PCs) of varying chain lengths, including PC 14:1, PC 18:1, PC 22:1, PC 24:1, and with porcine brain sphingomyelin. Bilayer thickness and structure was measured with small angle x-ray diffraction and atomic force microscopy. The open probability (P(o)) of the BK(Ca) channel was finely tuned by bilayer thickness, first decreasing with increases in bilayer thickness from PC 14:1 to PC 22:1 and then increasing from PC 22:1 to PC 24:1 and to porcine brain sphingomyelin. Single channel kinetic analyses revealed that the mean open time of the channel increased monotonically with bilayer thickness and, therefore, could not account for the biphasic changes in P(o). The mean closed time increased with bilayer thickness from PC 14:1 up to PC 22:1 and then decreased with further increases in bilayer thickness to PC 24:1 and sphingomyelin, correlating with changes in P(o). This is consistent with the proposition that bilayer thickness affects channel activity mainly through altering the stability of the closed state. We suggest a simple mechanical model that combines forces of lateral stress within the lipid bilayer with local hydrophobic mismatch between lipids and the protein to account for the biphasic modulation of BK(Ca) gating.
Highlights
Ion channel proteins play an important role in the regulation of ion fluxes across cell and organelle membranes
The opening and closing of ion channels is sensitive to changes in the physical properties of the lipid bilayer, such as lipid composition [1, 2], bilayer thickness [3, 4], surface charge [5], and lateral stress [6], which provide mechanisms through which lipid bilayers regulate the function of resident ion channels
BKCa channels possess many of the common structural features of homotetrameric voltagegated Kϩ channels, including an ion-selective pore formed by transmembrane segments S5 and S6 and a voltage-sensing module formed by transmembrane segments S1-S4
Summary
The conductance and open probability of BKCa channels was shown to be increased in lipid bilayers enriched with negatively charged lipids [31], an effect attributed to differences in surface charges leading to alterations of local concentrations of Ca2ϩ and Kϩ [5, 32]. This conclusion, was revised in a recent study using Ba2ϩ to block the BKCa channel. The model suggests that at least two processes account for the influence of bilayer thickness on BK channel kinetics and open probability; lateral stress seems to predominate in thinner bilayers, whereas hydrophobic mismatch seems to be the primary determinant of the effect in thicker bilayers
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