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Cystic fibrosis transmembrane conductance regulator. Physical basis for lyotropic anion selectivity patterns.

Smith SS, Steinle ED, Meyerhoff ME, Dawson DC - J. Gen. Physiol. (1999)

Bottom Line: The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19.These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative.Anions that are smaller (more difficult to dehydrate) than Cl are energetically retarded from entering the channel, while the larger (more readily dehydrated) anions are retarded in their passage by "sticking" within the channel.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel exhibits lyotropic anion selectivity. Anions that are more readily dehydrated than Cl exhibit permeability ratios (P(S)/P(Cl)) greater than unity and also bind more tightly in the channel. We compared the selectivity of CFTR to that of a synthetic anion-selective membrane [poly(vinyl chloride)-tridodecylmethylammonium chloride; PVC-TDMAC] for which the nature of the physical process that governs the anion-selective response is more readily apparent. The permeability and binding selectivity patterns of CFTR differed only by a multiplicative constant from that of the PVC-TDMAC membrane; and a continuum electrostatic model suggested that both patterns could be understood in terms of the differences in the relative stabilization of anions by water and the polarizable interior of the channel or synthetic membrane. The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19. The model predicts that large anions, like SCN, although they experience weaker interactions (relative to Cl) with water and also with the channel, are more permeant than Cl because anion-water energy is a steeper function of 1/r than is the anion-channel energy. These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative. This simple selectivity mechanism that governs permeability and binding acts to optimize the function of CFTR as a Cl filter. Anions that are smaller (more difficult to dehydrate) than Cl are energetically retarded from entering the channel, while the larger (more readily dehydrated) anions are retarded in their passage by "sticking" within the channel.

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Energetics of permeability selectivity for GABAR (A), GlyR (B), and the T84-ORCC (C). The filled circles represent the relative peak heights [Δ(ΔG)peak, SCN reference] calculated from the reported permeability ratios (Bormann et al. 1987; Halm and Frizzell 1992) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, SCN reference] calculated using  vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
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Figure 5: Energetics of permeability selectivity for GABAR (A), GlyR (B), and the T84-ORCC (C). The filled circles represent the relative peak heights [Δ(ΔG)peak, SCN reference] calculated from the reported permeability ratios (Bormann et al. 1987; Halm and Frizzell 1992) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, SCN reference] calculated using vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.

Mentions: Fig. 5 A contains data taken from the analysis of Bormann et al. 1987 of relative anion permeability in the GABA receptor (GABAR). The pattern of permeability selectivity for the ligand-gated channel also conforms to the predictions of a continuum electrostatic model, where the anion–pore interaction is modeled as the stabilization of an anion by a polarizable medium. The effective dielectric constant is predicted to be somewhat lower than that of CFTR, ∼12.4, because the selectivity is somewhat higher. The absolute barrier for Cl is predicted to be 19.6 kJ/mol (7.9 RT), which agrees fairly well with the estimates of Bormann et al. 1987 of a barrier height of 24 kJ/mol (9.7 RT) for a three-barrier, two-site model. A similar analysis of the glycine receptor (GlyR; Bormann et al. 1987) and the outwardly rectifying chloride channel (ORCC) from T-84 cells (Halm and Frizzell 1992) is shown in Fig. 5B and Fig. C, respectively.


Cystic fibrosis transmembrane conductance regulator. Physical basis for lyotropic anion selectivity patterns.

Smith SS, Steinle ED, Meyerhoff ME, Dawson DC - J. Gen. Physiol. (1999)

Energetics of permeability selectivity for GABAR (A), GlyR (B), and the T84-ORCC (C). The filled circles represent the relative peak heights [Δ(ΔG)peak, SCN reference] calculated from the reported permeability ratios (Bormann et al. 1987; Halm and Frizzell 1992) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, SCN reference] calculated using  vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230651&req=5

Figure 5: Energetics of permeability selectivity for GABAR (A), GlyR (B), and the T84-ORCC (C). The filled circles represent the relative peak heights [Δ(ΔG)peak, SCN reference] calculated from the reported permeability ratios (Bormann et al. 1987; Halm and Frizzell 1992) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, SCN reference] calculated using vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
Mentions: Fig. 5 A contains data taken from the analysis of Bormann et al. 1987 of relative anion permeability in the GABA receptor (GABAR). The pattern of permeability selectivity for the ligand-gated channel also conforms to the predictions of a continuum electrostatic model, where the anion–pore interaction is modeled as the stabilization of an anion by a polarizable medium. The effective dielectric constant is predicted to be somewhat lower than that of CFTR, ∼12.4, because the selectivity is somewhat higher. The absolute barrier for Cl is predicted to be 19.6 kJ/mol (7.9 RT), which agrees fairly well with the estimates of Bormann et al. 1987 of a barrier height of 24 kJ/mol (9.7 RT) for a three-barrier, two-site model. A similar analysis of the glycine receptor (GlyR; Bormann et al. 1987) and the outwardly rectifying chloride channel (ORCC) from T-84 cells (Halm and Frizzell 1992) is shown in Fig. 5B and Fig. C, respectively.

Bottom Line: The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19.These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative.Anions that are smaller (more difficult to dehydrate) than Cl are energetically retarded from entering the channel, while the larger (more readily dehydrated) anions are retarded in their passage by "sticking" within the channel.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel exhibits lyotropic anion selectivity. Anions that are more readily dehydrated than Cl exhibit permeability ratios (P(S)/P(Cl)) greater than unity and also bind more tightly in the channel. We compared the selectivity of CFTR to that of a synthetic anion-selective membrane [poly(vinyl chloride)-tridodecylmethylammonium chloride; PVC-TDMAC] for which the nature of the physical process that governs the anion-selective response is more readily apparent. The permeability and binding selectivity patterns of CFTR differed only by a multiplicative constant from that of the PVC-TDMAC membrane; and a continuum electrostatic model suggested that both patterns could be understood in terms of the differences in the relative stabilization of anions by water and the polarizable interior of the channel or synthetic membrane. The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19. The model predicts that large anions, like SCN, although they experience weaker interactions (relative to Cl) with water and also with the channel, are more permeant than Cl because anion-water energy is a steeper function of 1/r than is the anion-channel energy. These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative. This simple selectivity mechanism that governs permeability and binding acts to optimize the function of CFTR as a Cl filter. Anions that are smaller (more difficult to dehydrate) than Cl are energetically retarded from entering the channel, while the larger (more readily dehydrated) anions are retarded in their passage by "sticking" within the channel.

Show MeSH
Related in: MedlinePlus