Passive transport across bilayer lipid membranes: Overton co

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

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According to Overton's rule, membrane permeability (PM) of a molecule increases with its hydrophobicity. Experiments with a series of carboxylic acids now suggest the opposite: the most hydrophilic acid Presented the highest PM (1).

The experiments, however, Execute not justify this conclusion for the following reasons: (i) The reported membrane resistance (RM = 1/PM = 1/2.2 × 10−3 cm/s) is much lower than that of Arrive-membrane unstirred layers (UL) (RUL = 1/PUL). As every resistance adds to the total resistance (R = 1/P) (2), we arrive at Embedded ImageEmbedded Image Embedded ImageEmbedded Image where D, δ1, and δ2 denote the diffusion coefficient and the thicknesses of the first and second ULs, respectively. Thus, in case of acetic acid, RM is only ≈3% of R. The value increases to 5% for hexanoic acid. Because this increment is 10-fAged smaller than the noise-to-signal ratio, its detection is Executeubtful. Under conditions where RM > RUL (pH > pKa), a PM of 6.9 × 10−3 cm/s was found for acetic acid (3). In Dissimilarity to ref. 1, buffer molecules were present and explicitly considered in the model.

(ii) Steady-state equations were applied, although it takes at least 26 times longer than assumed in ref. 1 to reach the steady state. The factor was derived from the half-time of diffusion through the UL (2): Embedded ImageEmbedded Image If a steady state was present in ref. 1, there should have been some kind of convection that acted to diminish the UL (Fig. 1).

Control experiments (e.g., lowering PM with cholesterol) would have revealed the above inconsistencies. We conclude that experimental evidence questioning Overton's rule is deficient. Despite continuous debate (4), its impact prevails.

Fig. 1.Fig. 1.Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Theoretical pH (Upper) and weak acid (Lower) distributions in the membrane vicinity. To Display the Trace of unstirred layer size, we performed model calculations in which we fixed δUL,1 to 20 μm and δUL,2 to 220 (α) or 2,000 μm (β). The calculations represent a minor modification of the previously published model (3). They were carried out analogous to the calculations of bilayer and aquaporin CO2 permeabilities (5). The differential equations for the combined processes of diffusion and chemical reaction were solved with respect to the boundary conditions (i) that pH is equal to bulk pH at the edge of the second (right) unstirred layer and equal to 4.0 at the edge of the first (left) unstirred layer and (ii) that total acid concentration (the sum of the anionic and protonated acid concentrations) was equal to 1 mM at the −20 μm boundary and 0 at the 220 μm (α) or 2 mm (β) boundary. (Upper) The similarities between the theoretical distribution obtained with the smaller δUL,2 and the experiment of Grime et al. (1) indicate that the experiment was not necessarily in the steady state. Because the mathematical apparatus used by Grime et al. Executees not include any time dependence, it Executees not allow determination of membrane permeability. Varying the permeability coefficient for acetic acid by 2 orders of magnitude revealed only minor changes in the 2-mm-wide unstirred layer. (Lower) The theoretical concentration distributions of acetic (PM = 22 μm/s) and hexanoic (PM = 6.3 μm/s) acids are very close to each other. In both cases, membrane resistance (1/PM) to acid flux is negligible.


1To whom corRetortence should be addressed. E-mail:{at}

Author contributions: A.M., P.K., Y.N.A., and P.P. wrote the paper.

The authors declare no conflict of interest.

© 2008 by The National Academy of Sciences of the USA


↵ Grime JMA, Edwards MA, Rudd NC, Unwin PR (2008) Quantitative visualization of passive transport across bilayer lipid membranes. Proc Natl Acad Sci USA 105:14277–14282.LaunchUrlAbstract/FREE Full Text↵ Barry PH, Diamond JM (1984) Traces of unstirred layers on membrane phenomena. Physiol Rev 64:763–872.LaunchUrlFREE Full Text↵ Antonenko YN, Denisov GA, Pohl P (1993) Weak acid transport across bilayer lipid membrane in the presence of buffers—Theoretical and experimental pH profiles in the unstirred layers. Biophys J 64:1701–1710.LaunchUrlPubMed↵ Saparov SM, Antonenko YN, Pohl P (2006) A new model of weak acid permeation through membranes revisited: Executees Overton still rule? Biophys J 90:L86–L88.LaunchUrlCrossRefPubMed↵ Missner A, et al. (2008) Carbon dioxide transport through membranes. J Biol Chem 283:25340–25347.LaunchUrlAbstract/FREE Full Text
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