| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received March 21, 2002
Accepted after revision May 21, 2002
1 The Cardiac Electrophysiology Laboratories, Departments of Medicine and of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 606037, USA
2 MC6094, University of Chicago Hospitals, 5841 South Maryland Avenue, Chicago, IL 60637, USA
* To whom correspondence should be addressed. E-mail: foz{at}hearts.bsd.uchicago.edu.
Voltage-gated Na+ current is reduced by acid solution. Protons reduce peak Na+ conductance by lowering single channel conductance and shift the voltage range of gating by neutralizing surface charges. Structure-function studies identify six carboxyls and a lysine in the channel's outer vestibule. We examined the roles of the superficial ring of carboxyls in acid block of Nav1.4 (the rat skeletal muscle Na+ channel isoform) by measuring the effects of their neutralization or their substitution by lysine on sensitivity to acid solutions, using the two-micropipette voltage clamp in Xenopus oocytes. Alteration of the outer ring of carboxylates had little effect on the voltage for half-activation of Na+ current, as if they are distant from the channels' voltage sensors. The mutations did not abolish proton block; rather, they all shifted the pKa (-log of the dissociation constant) in the acid direction. Effects of neutralization on pKa were not identical for different mutations, with E758Q > D1241A > D1532N > E403Q. E758K showed double the effect of E758Q, and the other lysine mutations were all larger than neutralization. Calculation of the electrostatic potential produced by these carboxylates using a pore model showed that the pKa values of carboxylates of Glu-403, Glu-758, and Asp-1532 are shifted to values similar to the experimentally measured pKa. Calculations also predict the experimentally observed changes in pKa that result from mutational neutralization or introduction of a positive charge. We propose that proton block results from partial protonation of these outer ring carboxylates and that all of the carboxylates contribute to a composite Na+ site.
This article has been cited by other articles:
|
|
 |
|
  G. M. Lipkind and H. A. Fozzard Voltage-gated Na Channel Selectivity: The Role of the Conserved Domain III Lysine Residue J. Gen. Physiol., June 1, 2008; 131(6): 523 - 529. [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. McNulty, G. B. Edgerton, R. D. Shah, D. A. Hanck, H. A. Fozzard, and G. M. Lipkind Charge at the lidocaine binding site residue Phe-1759 affects permeation in human cardiac voltage-gated sodium channels J. Physiol., June 1, 2007; 581(2): 741 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xiong, Y. Z. Farukhi, Y. Tian, D. DiSilvestre, R. A. Li, and G. F. Tomaselli A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation J. Physiol., November 1, 2006; 576(3): 739 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khan, J. W. Kyle, D. A. Hanck, G. M. Lipkind, and H. A. Fozzard Isoform-dependent interaction of voltage-gated sodium channels with protons J. Physiol., October 15, 2006; 576(2): 493 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Musset, S. G. Meuth, G. X. Liu, C. Derst, S. Wegner, H.-C. Pape, T. Budde, R. Preisig-Muller, and J. Daut Effects of divalent cations and spermine on the K+ channel TASK-3 and on the outward current in thalamic neurons J. Physiol., May 1, 2006; 572(3): 639 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Lipkind and H. A. Fozzard Molecular Modeling of Local Anesthetic Drug Binding by Voltage-Gated Sodium Channels Mol. Pharmacol., December 1, 2005; 68(6): 1611 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. B. Tikhonov and B. S. Zhorov Modeling P-Loops Domain of Sodium Channel: Homology with Potassium Channels and Interaction with Ligands Biophys. J., January 1, 2005; 88(1): 184 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-I. Yeh, T.-J. Sun, J. Z. Lee, H.-H. Chen, and C.-L. Huang Mechanism and Molecular Determinant for Regulation of Rabbit Transient Receptor Potential Type 5 (TRPV5) Channel by Extracellular pH J. Biol. Chem., December 19, 2003; 278(51): 51044 - 51052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hui, D. McIntyre, and R. J. French Conotoxins as Sensors of Local pH and Electrostatic Potential in the Outer Vestibule of the Sodium Channel J. Gen. Physiol., June 30, 2003; 122(1): 63 - 79. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
