Original Article

Cystic Fibrosis Transmembrane Conductance Regulator: Physical Basis for Lyotropic Anion Selectivity Patterns

Correspondence to: David C. Dawson, Department of Physiology & Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., L-334, Portland, OR 97201. Fax:503-494-4352 E-mail:dawsonda{at}ohsu.edu.

Released online: 29 November 1999

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.

Key Words: hydration energy, anion binding, pseudohalides, ion-selective electrodes, anion channels

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Fatehi and P. Linsdell State-dependent Access of Anions to the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore J. Biol. Chem., March 7, 2008; 283(10): 6102 - 6109. [Abstract] [Full Text] [PDF]

				M. D. Parker, M. T. Young, C. M. Daly, R. W. Meech, W. F. Boron, and M. J. A. Tanner A conductive pathway generated from fragments of the human red cell anion exchanger AE1 J. Physiol., May 15, 2007; 581(1): 33 - 50. [Abstract] [Full Text] [PDF]

				M. Fatehi, C. N. St. Aubin, and P. Linsdell On the Origin of Asymmetric Interactions between Permeant Anions and the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore Biophys. J., February 15, 2007; 92(4): 1241 - 1253. [Abstract] [Full Text] [PDF]

				L. G. Palmer and G. Frindt Cl- channels of the distal nephron Am J Physiol Renal Physiol, December 1, 2006; 291(6): F1157 - F1168. [Abstract] [Full Text] [PDF]

				J. R. Serrano, X. Liu, E. R. Borg, C. S. Alexander, C. F. Shaw 3rd, and D. C. Dawson CFTR: Ligand Exchange between a Permeant Anion ([Au(CN)2]-) and an Engineered Cysteine (T338C) Blocks the Pore Biophys. J., September 1, 2006; 91(5): 1737 - 1748. [Abstract] [Full Text] [PDF]

				X. Liu, C. Alexander, J. Serrano, E. Borg, and D. C. Dawson Variable Reactivity of an Engineered Cysteine at Position 338 in Cystic Fibrosis Transmembrane Conductance Regulator Reflects Different Chemical States of the Thiol J. Biol. Chem., March 24, 2006; 281(12): 8275 - 8285. [Abstract] [Full Text] [PDF]

				P. Linsdell Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel Exp Physiol, January 1, 2006; 91(1): 123 - 129. [Abstract] [Full Text] [PDF]

				K. Liu, D. Kozono, Y. Kato, P. Agre, A. Hazama, and M. Yasui From The Cover: Conversion of aquaporin 6 from an anion channel to a water-selective channel by a single amino acid substitution PNAS, February 8, 2005; 102(6): 2192 - 2197. [Abstract] [Full Text] [PDF]

				X. Liu, Z.-R. Zhang, M. D. Fuller, J. Billingsley, N. A. McCarty, and D. C. Dawson CFTR: A Cysteine at Position 338 in TM6 Senses a Positive Electrostatic Potential in the Pore Biophys. J., December 1, 2004; 87(6): 3826 - 3841. [Abstract] [Full Text] [PDF]

				Z. Qu and C. Hartzell Determinants of Anion Permeation in the Second Transmembrane Domain of the Mouse Bestrophin-2 Chloride Channel J. Gen. Physiol., September 27, 2004; 124(4): 371 - 382. [Abstract] [Full Text] [PDF]

				R. M. Ryan, A. D. Mitrovic, and R. J. Vandenberg The Chloride Permeation Pathway of a Glutamate Transporter and Its Proximity to the Glutamate Translocation Pathway J. Biol. Chem., May 14, 2004; 279(20): 20742 - 20751. [Abstract] [Full Text] [PDF]

				Z. Qu, R. Fischmeister, and C. Hartzell Mouse Bestrophin-2 Is a Bona fide Cl- Channel: Identification of a Residue Important in Anion Binding and Conduction J. Gen. Physiol., March 29, 2004; 123(4): 327 - 340. [Abstract] [Full Text] [PDF]

				X. Gong and P. Linsdell Mutation-induced Blocker Permeability and Multiion Block of the CFTR Chloride Channel Pore J. Gen. Physiol., November 24, 2003; 122(6): 673 - 687. [Abstract] [Full Text] [PDF]

				Z. Zhou, S. Hu, and T.-C. Hwang Probing an Open CFTR Pore with Organic Anion Blockers J. Gen. Physiol., October 29, 2002; 120(5): 647 - 662. [Abstract] [Full Text] [PDF]

				N. A. McCarty and Z.-R. Zhang Identification of a region of strong discrimination in the pore of CFTR Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L852 - L867. [Abstract] [Full Text] [PDF]

				K. O'Connor and K. Beyenbach Chloride channels in apical membrane patches of stellate cells of Malpighian tubules of Aedes aegypti J. Exp. Biol., January 1, 2001; 204(2): 367 - 378. [Abstract] [PDF]

				N. McCarty Permeation through the CFTR chloride channel J. Exp. Biol., January 7, 2000; 203(13): 1947 - 1962. [Abstract] [PDF]

				P. Linsdell and X. Gong Multiple inhibitory effects of Au(CN)2- ions on cystic fibrosis transmembrane conductance regulator Cl- channel currents J. Physiol., April 1, 2002; 540(1): 29 - 38. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents