We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Isoform-dependent interaction of voltage-gated sodium channels with protons.
- Authors
Khan, A.; Kyle, J. W.; Hanck, D. A.; Lipkind, G. M.; Fozzard, H. A.
- Abstract
Protons are potent physiological modifiers of voltage-gated Na+ channels, shifting the voltage range of channel gating and reducing current magnitude (p Ka∼6). We recently showed that proton block of the skeletal muscle isoform (NaV1.4) resulted from protonation of the four superficial carboxylates in the outer vestibule of the channel. We concluded that the large local negative electrostatic field shifted the outer vestibule carboxylate p Ka into the physiological range. However, block was not complete; the best-fit titration curves yielded an acid pH asymptote of 10–15%, suggesting that the selectivity filter carboxylates may not be protonated. Using HEK 293 cells stably expressing different isoforms, each with varying channel density, we demonstrate that a pH-independent current is found in NaV1.4, but not in the cardiac isoform (NaV1.5). Mutational studies showed that absence of the pH-independent current in NaV1.5 could be ascribed to the cysteine in domain I, just above the selectivity filter aspartate (Cys373). We suggest that this cysteine can be protonated in acid solution to produce a positive charge that blocks the pore. Competition between protons and Na+ did not exist for Na+ concentrations between 1 and 140 mm. The residual current in acid solution, when the cysteine is absent, confirms that over the range of pH values that can be achieved physiologically, the selectivity filter carboxylates are not protonated. The pH-independent current helps to protect activation of skeletal muscle during the acidosis that occurs during exercise.
- Subjects
SODIUM channels; PROTONS; VOLTAGE regulators; HYDROGEN-ion concentration; MUSCULOSKELETAL system
- Publication
Journal of Physiology, 2006, Vol 576, Issue 2, p493
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/jphysiol.2006.115659