Skip to main content
Biophysical Journal logoLink to Biophysical Journal
. 1998 Sep;75(3):1287–1305. doi: 10.1016/S0006-3495(98)74048-2

Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels.

W Nonner 1, B Eisenberg 1
PMCID: PMC1299804  PMID: 9726931

Abstract

L-type Ca channels contain a cluster of four charged glutamate residues (EEEE locus), which seem essential for high Ca specificity. To understand how this highly charged structure might produce the currents and selectivity observed in this channel, a theory is needed that relates charge to current. We use an extended Poisson-Nernst-Planck (PNP2) theory to compute (mean) Coulombic interactions and thus to examine the role of the mean field electrostatic interactions in producing current and selectivity. The pore was modeled as a central cylinder with tapered atria; the cylinder (i.e., "pore proper") contained a uniform volume density of fixed charge equivalent to that of one to four carboxyl groups. The pore proper was assigned ion-specific, but spatially uniform, diffusion coefficients and excess chemical potentials. Thus electrostatic selection by valency was computed self-consistently, and selection by other features was also allowed. The five external parameters needed for a system of four ionic species (Na, Ca, Cl, and H) were determined analytically from published measurements of thre limiting conductances and two critical ion concentrations, while treating the pore as a macroscopic ion-exchange system in equilibrium with a uniform bath solution. The extended PNP equations were solved with these parameters, and the predictions were compared to currents measured in a variety of solutions over a range of transmembrane voltages. The extended PNP theory accurately predicted current-voltage relations, anomalous mole fraction effects in the observed current, saturation effects of varied Ca and Na concentrations, and block by protons. Pore geometry, dielectric permittivity, and the number of carboxyl groups had only weak effects. The successful prediction of Ca fluxes in this paper demonstrates that ad hoc electrostatic parameters, multiple discrete binding sites, and logistic assumptions of single-file movement are all unnecessary for the prediction of permeation in Ca channels over a wide range of conditions. Further work is needed, however, to understand the atomic origin of the fixed charge, excess chemical potentials, and diffusion coefficients of the channel. The Appendix uses PNP2 theory to predict ionic currents for published "barrier-and-well" energy profiles of this channel.

Full Text

The Full Text of this article is available as a PDF (344.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almers W., McCleskey E. W. Non-selective conductance in calcium channels of frog muscle: calcium selectivity in a single-file pore. J Physiol. 1984 Aug;353:585–608. doi: 10.1113/jphysiol.1984.sp015352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Almers W., McCleskey E. W., Palade P. T. A non-selective cation conductance in frog muscle membrane blocked by micromolar external calcium ions. J Physiol. 1984 Aug;353:565–583. doi: 10.1113/jphysiol.1984.sp015351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Armstrong C. M., Neyton J. Ion permeation through calcium channels. A one-site model. Ann N Y Acad Sci. 1991;635:18–25. doi: 10.1111/j.1749-6632.1991.tb36477.x. [DOI] [PubMed] [Google Scholar]
  4. Barkai E, Eisenberg RS, Schuss Z. Bidirectional shot noise in a singly occupied channel. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 1996 Aug;54(2):1161–1175. doi: 10.1103/physreve.54.1161. [DOI] [PubMed] [Google Scholar]
  5. Chen D., Eisenberg R. Charges, currents, and potentials in ionic channels of one conformation. Biophys J. 1993 May;64(5):1405–1421. doi: 10.1016/S0006-3495(93)81507-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen D., Lear J., Eisenberg B. Permeation through an open channel: Poisson-Nernst-Planck theory of a synthetic ionic channel. Biophys J. 1997 Jan;72(1):97–116. doi: 10.1016/S0006-3495(97)78650-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chen D., Xu L., Tripathy A., Meissner G., Eisenberg B. Permeation through the calcium release channel of cardiac muscle. Biophys J. 1997 Sep;73(3):1337–1354. doi: 10.1016/S0006-3495(97)78167-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chen X. H., Bezprozvanny I., Tsien R. W. Molecular basis of proton block of L-type Ca2+ channels. J Gen Physiol. 1996 Nov;108(5):363–374. doi: 10.1085/jgp.108.5.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dang T. X., McCleskey E. W. Ion channel selectivity through stepwise changes in binding affinity. J Gen Physiol. 1998 Feb;111(2):185–193. doi: 10.1085/jgp.111.2.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dani J. A. Ion-channel entrances influence permeation. Net charge, size, shape, and binding considerations. Biophys J. 1986 Mar;49(3):607–618. doi: 10.1016/S0006-3495(86)83688-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Das S., Lengweiler U. D., Seebach D., Reusch R. N. Proof for a nonproteinaceous calcium-selective channel in Escherichia coli by total synthesis from (R)-3-hydroxybutanoic acid and inorganic polyphosphate. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9075–9079. doi: 10.1073/pnas.94.17.9075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eisenberg R. S. Computing the field in proteins and channels. J Membr Biol. 1996 Mar;150(1):1–25. doi: 10.1007/s002329900026. [DOI] [PubMed] [Google Scholar]
  13. Eisenman G., Latorre R., Miller C. Multi-ion conduction and selectivity in the high-conductance Ca++-activated K+ channel from skeletal muscle. Biophys J. 1986 Dec;50(6):1025–1034. doi: 10.1016/S0006-3495(86)83546-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ellinor P. T., Yang J., Sather W. A., Zhang J. F., Tsien R. W. Ca2+ channel selectivity at a single locus for high-affinity Ca2+ interactions. Neuron. 1995 Nov;15(5):1121–1132. doi: 10.1016/0896-6273(95)90100-0. [DOI] [PubMed] [Google Scholar]
  15. Heinemann S. H., Terlau H., Stühmer W., Imoto K., Numa S. Calcium channel characteristics conferred on the sodium channel by single mutations. Nature. 1992 Apr 2;356(6368):441–443. doi: 10.1038/356441a0. [DOI] [PubMed] [Google Scholar]
  16. Hess P., Lansman J. B., Tsien R. W. Calcium channel selectivity for divalent and monovalent cations. Voltage and concentration dependence of single channel current in ventricular heart cells. J Gen Physiol. 1986 Sep;88(3):293–319. doi: 10.1085/jgp.88.3.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hess P., Tsien R. W. Mechanism of ion permeation through calcium channels. 1984 May 31-Jun 6Nature. 309(5967):453–456. doi: 10.1038/309453a0. [DOI] [PubMed] [Google Scholar]
  18. Hille B., Schwarz W. Potassium channels as multi-ion single-file pores. J Gen Physiol. 1978 Oct;72(4):409–442. doi: 10.1085/jgp.72.4.409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jordan P. C., Bacquet R. J., McCammon J. A., Tran P. How electrolyte shielding influences the electrical potential in transmembrane ion channels. Biophys J. 1989 Jun;55(6):1041–1052. doi: 10.1016/S0006-3495(89)82903-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kim M. S., Morii T., Sun L. X., Imoto K., Mori Y. Structural determinants of ion selectivity in brain calcium channel. FEBS Lett. 1993 Mar 1;318(2):145–148. doi: 10.1016/0014-5793(93)80009-j. [DOI] [PubMed] [Google Scholar]
  21. Lansman J. B., Hess P., Tsien R. W. Blockade of current through single calcium channels by Cd2+, Mg2+, and Ca2+. Voltage and concentration dependence of calcium entry into the pore. J Gen Physiol. 1986 Sep;88(3):321–347. doi: 10.1085/jgp.88.3.321. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lee K. S., Tsien R. W. High selectivity of calcium channels in single dialysed heart cells of the guinea-pig. J Physiol. 1984 Sep;354:253–272. doi: 10.1113/jphysiol.1984.sp015374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McCleskey E. W., Almers W. The Ca channel in skeletal muscle is a large pore. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7149–7153. doi: 10.1073/pnas.82.20.7149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mikala G., Bahinski A., Yatani A., Tang S., Schwartz A. Differential contribution by conserved glutamate residues to an ion-selectivity site in the L-type Ca2+ channel pore. FEBS Lett. 1993 Dec 6;335(2):265–269. doi: 10.1016/0014-5793(93)80743-e. [DOI] [PubMed] [Google Scholar]
  25. Mikami A., Imoto K., Tanabe T., Niidome T., Mori Y., Takeshima H., Narumiya S., Numa S. Primary structure and functional expression of the cardiac dihydropyridine-sensitive calcium channel. Nature. 1989 Jul 20;340(6230):230–233. doi: 10.1038/340230a0. [DOI] [PubMed] [Google Scholar]
  26. Nonner W., Chen D. P., Eisenberg B. Anomalous mole fraction effect, electrostatics, and binding in ionic channels. Biophys J. 1998 May;74(5):2327–2334. doi: 10.1016/S0006-3495(98)77942-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Peskoff A., Bers D. M. Electrodiffusion of ions approaching the mouth of a conducting membrane channel. Biophys J. 1988 Jun;53(6):863–875. doi: 10.1016/S0006-3495(88)83167-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pietrobon D., Prod'hom B., Hess P. Interactions of protons with single open L-type calcium channels. pH dependence of proton-induced current fluctuations with Cs+, K+, and Na+ as permeant ions. J Gen Physiol. 1989 Jul;94(1):1–21. doi: 10.1085/jgp.94.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Prod'hom B., Pietrobon D., Hess P. Interactions of protons with single open L-type calcium channels. Location of protonation site and dependence of proton-induced current fluctuations on concentration and species of permeant ion. J Gen Physiol. 1989 Jul;94(1):23–42. doi: 10.1085/jgp.94.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reusch R. N., Huang R., Bramble L. L. Poly-3-hydroxybutyrate/polyphosphate complexes form voltage-activated Ca2+ channels in the plasma membranes of Escherichia coli. Biophys J. 1995 Sep;69(3):754–766. doi: 10.1016/S0006-3495(95)79958-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tanabe T., Takeshima H., Mikami A., Flockerzi V., Takahashi H., Kangawa K., Kojima M., Matsuo H., Hirose T., Numa S. Primary structure of the receptor for calcium channel blockers from skeletal muscle. Nature. 1987 Jul 23;328(6128):313–318. doi: 10.1038/328313a0. [DOI] [PubMed] [Google Scholar]
  32. Tsien R. W., Hess P., McCleskey E. W., Rosenberg R. L. Calcium channels: mechanisms of selectivity, permeation, and block. Annu Rev Biophys Biophys Chem. 1987;16:265–290. doi: 10.1146/annurev.bb.16.060187.001405. [DOI] [PubMed] [Google Scholar]
  33. Yang J., Ellinor P. T., Sather W. A., Zhang J. F., Tsien R. W. Molecular determinants of Ca2+ selectivity and ion permeation in L-type Ca2+ channels. Nature. 1993 Nov 11;366(6451):158–161. doi: 10.1038/366158a0. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES