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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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(A) CFTR permeability selectivity and PVC-TDMAC membrane selectivity. CFTR permeability ratios (Table ) expressed as differences in the peak heights (kJ/mol) plotted as a function of Δ(ΔG)trans for the PVC-TDMAC membrane, which has the units of kilojoules per mole (see ). Both variables are defined with respect to tricyanomethanide, so that the y and x axes reflect, respectively, the magnitude of the increase in the apparent peak barrier height and the increase in the water-electrode transfer free energy. The line shown is a linear regression with a slope of 0.16 and correlation coefficient (r2) of 0.93. The iodide point (○) flagged with an asterisk reflects a PI/PCl of 2.1, as determined by Tabcharani et al. 1997, whereas the lower value (□), PI/PCl of 0.4, flagged with a double asterisk, is more often seen with CFTR (Anderson et al. 1991; Sheppard et al. 1993; Mansoura et al. 1998). (B) CFTR binding selectivity and PVC-TDMAC membrane selectivity. The ratio of the apparent half-maximal inhibition constants expressed as relative differences in well depth (kJ/mol) are plotted as a function of Δ(ΔG)trans for the PVC-TDMAC (kJ/mol). Both variables are defined with respect to tricyanomethanide. The line shown is a linear regression with a slope of 0.196 and a correlation coefficient of 0.73.
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Figure 2: (A) CFTR permeability selectivity and PVC-TDMAC membrane selectivity. CFTR permeability ratios (Table ) expressed as differences in the peak heights (kJ/mol) plotted as a function of Δ(ΔG)trans for the PVC-TDMAC membrane, which has the units of kilojoules per mole (see ). Both variables are defined with respect to tricyanomethanide, so that the y and x axes reflect, respectively, the magnitude of the increase in the apparent peak barrier height and the increase in the water-electrode transfer free energy. The line shown is a linear regression with a slope of 0.16 and correlation coefficient (r2) of 0.93. The iodide point (○) flagged with an asterisk reflects a PI/PCl of 2.1, as determined by Tabcharani et al. 1997, whereas the lower value (□), PI/PCl of 0.4, flagged with a double asterisk, is more often seen with CFTR (Anderson et al. 1991; Sheppard et al. 1993; Mansoura et al. 1998). (B) CFTR binding selectivity and PVC-TDMAC membrane selectivity. The ratio of the apparent half-maximal inhibition constants expressed as relative differences in well depth (kJ/mol) are plotted as a function of Δ(ΔG)trans for the PVC-TDMAC (kJ/mol). Both variables are defined with respect to tricyanomethanide. The line shown is a linear regression with a slope of 0.196 and a correlation coefficient of 0.73.

Mentions: In Fig. 2, the energy differences associated with anion permeation (A) and block (B) are plotted versus the corresponding energies derived from the response of the PVC-TDMAC membrane. The high correlation of these values (with the exception of iodide, see below) indicates that the selectivity pattern exhibited by CFTR, as judged by either relative permeability or relative binding, is qualitatively identical to that of the synthetic membrane, differing in each case only by a multiplicative constant. Anions that see a barrier height that is increased relative to that of C(CN)3 also experience a more positive (less favorable) transfer free energy between water and the synthetic membrane. Similarly, anions that bind less tightly than C(CN)3 are those for which the water-synthetic membrane transfer free energy is less favorable. It is apparent from Fig. 2 that the peak and well energies change in a parallel fashion. SCN, for example, sees an energy barrier to entering the CFTR channel that is lower than that of Cl, and also sees an equilibrium free energy associated with partitioning into the synthetic membrane that is more favorable than that of Cl. Similarly, the tighter binding of SCN (relative to Cl) is correlated with ease of partitioning into the synthetic membrane. These results are, perhaps, not surprising in that the selectivity patterns for both CFTR and the PVC-TDMAC membrane have both been previously identified as being consistent with the “lyotropic” or Hofmeister series, which is ordered according to relative free energy of hydration (Anderson et al. 1991; Linsdell et al. 1997a,Linsdell et al. 1997b; Tabcharani et al., 1997b). Anions that are more readily dehydrated than Cl exhibit higher permeability ratios and bind more tightly within the CFTR pore, and also partition more readily into the PVC-TDMAC membrane.


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

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

(A) CFTR permeability selectivity and PVC-TDMAC membrane selectivity. CFTR permeability ratios (Table ) expressed as differences in the peak heights (kJ/mol) plotted as a function of Δ(ΔG)trans for the PVC-TDMAC membrane, which has the units of kilojoules per mole (see ). Both variables are defined with respect to tricyanomethanide, so that the y and x axes reflect, respectively, the magnitude of the increase in the apparent peak barrier height and the increase in the water-electrode transfer free energy. The line shown is a linear regression with a slope of 0.16 and correlation coefficient (r2) of 0.93. The iodide point (○) flagged with an asterisk reflects a PI/PCl of 2.1, as determined by Tabcharani et al. 1997, whereas the lower value (□), PI/PCl of 0.4, flagged with a double asterisk, is more often seen with CFTR (Anderson et al. 1991; Sheppard et al. 1993; Mansoura et al. 1998). (B) CFTR binding selectivity and PVC-TDMAC membrane selectivity. The ratio of the apparent half-maximal inhibition constants expressed as relative differences in well depth (kJ/mol) are plotted as a function of Δ(ΔG)trans for the PVC-TDMAC (kJ/mol). Both variables are defined with respect to tricyanomethanide. The line shown is a linear regression with a slope of 0.196 and a correlation coefficient of 0.73.
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Figure 2: (A) CFTR permeability selectivity and PVC-TDMAC membrane selectivity. CFTR permeability ratios (Table ) expressed as differences in the peak heights (kJ/mol) plotted as a function of Δ(ΔG)trans for the PVC-TDMAC membrane, which has the units of kilojoules per mole (see ). Both variables are defined with respect to tricyanomethanide, so that the y and x axes reflect, respectively, the magnitude of the increase in the apparent peak barrier height and the increase in the water-electrode transfer free energy. The line shown is a linear regression with a slope of 0.16 and correlation coefficient (r2) of 0.93. The iodide point (○) flagged with an asterisk reflects a PI/PCl of 2.1, as determined by Tabcharani et al. 1997, whereas the lower value (□), PI/PCl of 0.4, flagged with a double asterisk, is more often seen with CFTR (Anderson et al. 1991; Sheppard et al. 1993; Mansoura et al. 1998). (B) CFTR binding selectivity and PVC-TDMAC membrane selectivity. The ratio of the apparent half-maximal inhibition constants expressed as relative differences in well depth (kJ/mol) are plotted as a function of Δ(ΔG)trans for the PVC-TDMAC (kJ/mol). Both variables are defined with respect to tricyanomethanide. The line shown is a linear regression with a slope of 0.196 and a correlation coefficient of 0.73.
Mentions: In Fig. 2, the energy differences associated with anion permeation (A) and block (B) are plotted versus the corresponding energies derived from the response of the PVC-TDMAC membrane. The high correlation of these values (with the exception of iodide, see below) indicates that the selectivity pattern exhibited by CFTR, as judged by either relative permeability or relative binding, is qualitatively identical to that of the synthetic membrane, differing in each case only by a multiplicative constant. Anions that see a barrier height that is increased relative to that of C(CN)3 also experience a more positive (less favorable) transfer free energy between water and the synthetic membrane. Similarly, anions that bind less tightly than C(CN)3 are those for which the water-synthetic membrane transfer free energy is less favorable. It is apparent from Fig. 2 that the peak and well energies change in a parallel fashion. SCN, for example, sees an energy barrier to entering the CFTR channel that is lower than that of Cl, and also sees an equilibrium free energy associated with partitioning into the synthetic membrane that is more favorable than that of Cl. Similarly, the tighter binding of SCN (relative to Cl) is correlated with ease of partitioning into the synthetic membrane. These results are, perhaps, not surprising in that the selectivity patterns for both CFTR and the PVC-TDMAC membrane have both been previously identified as being consistent with the “lyotropic” or Hofmeister series, which is ordered according to relative free energy of hydration (Anderson et al. 1991; Linsdell et al. 1997a,Linsdell et al. 1997b; Tabcharani et al., 1997b). Anions that are more readily dehydrated than Cl exhibit higher permeability ratios and bind more tightly within the CFTR pore, and also partition more readily into the PVC-TDMAC membrane.

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