Abstract
1. Using macropatch techniques, we tested the assumption that deactivation underlies the observed delay in the onset to recovery from fast inactivation by comparing open-state deactivation to recovery delay for rat skeletal muscle mutations R1441C and R1441P.
2. Deactivation kinetics from the open state were determined from the exponential decay of tail currents. R1441C and R1441P prolonged open-state deactivation, with the greatest effect produced by R1441P.
3. Delays in the onset to recovery from fast inactivation for R1441P and for R1441C were abbreviated compared to those for rSkM1. Recovery delay was longer in R1441P than R1441C at voltages more negative than −110 mV. Recovery from inactivation exhibited a voltage dependence which, unlike delay, saturated at depolarized voltages. Recovery rate constants were increased to a similar extent for R1441C and R1441P at −150 to −120 mV compared to rSkMl.
4. These results indicate that the delay in the onset to recovery from fast inactivation in skeletal muscle sodium channels is due to deactivation. Lessening of charge immobilization for R1441C and R1441P may contribute to observed biophysical defects underlying the hyperexcitability of muscle fibers containing paramyotonia congenita mutations. The second stage of recovery from fast inactivation may be affected differentially by these mutations.
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REFERENCES
Armstrong, C. M., and Bezanilla, F. (1974). Charge movement associated with the opening and closing of the activation gates of the Na channels. J. Gen. Physiol. 63:533-552.
Armstrong, C. M., and Bezanilla, F. (1977). Inactivation of the sodium channel. II. Gating current experiments. J. Gen. Physiol. 70:567-590.
Baker, O. S., Larsson, H. P., Mannuzzu, L. M., and Isacoff, E. Y. (1998). Three transmembrane conformations and sequence-dependent displacement of the S4 domain in Shaker channel K+ channel gating. Neuron 20:1283-1294.
Bendahhou, S., Cummins, T. R., Kwiecinski, H., Waxman, S. G., and Ptacek, L. J. (1999). Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia congenita in humans. J. Physiol. 518(2):337-344.
Cha, A., Ruben, P. C., George, A. L., Jr., Fujimoto, E., and Bezanilla, F. (1999). Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation. Neuron 22:73-87.
Chahine, M., George, A. L., Jr., Zhou, M., Ji, S., Sun, W., Barchi, R. L., and Horn, R. (1994). Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation. Neuron 12:281-294.
Featherstone, D. E., Fujimoto, E., and Ruben, P. C. (1998). A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita. J. Physiol. 506:627-638.
Groome, J. R., Fujimoto, E., George, A. L., Jr., and Ruben, P. C. (1999). Differential effects of homologous S4 mutations in human skeletal muscle sodium channels on deactivation gating from open and inactivated states. J. Physiol. 516(3):687-698.
Hodgkin, A. L., and Huxley, A. F. (1952). A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117:500-544.
Ji, S., George, A. L., Jr., Horn, R., and Barchi, R. L. (1996). Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating. J. Gen. Physiol. 107:183-194.
Kontis, K. J., Rounaghi, A., and Goldin, A. L. (1997). Sodium channel activation gating is affected by substitutions of voltage sensor positive charges in all four domains. J. Gen. Physiol. 110:391-401.
Kuhn, F. J. P., and Greef, N. G. (1999). Movement of voltage sensor S4 in domain 4 is tightly coupled to sodium channel fast inactivation and gating charge immobilization. J. Gen. Physiol. 114:167-183.
Kuo, C.-C., and Bean, B. P. (1994). Na+ channels must deactivate to recover from inactivation. Neuron 12:819-829.
Larsson, H. P., Baker, O. S., Dhillon, D. S., and Isacoff, E. Y. (1996). Transmembrane movement of the Shaker K+ channel S4. Neuron 16:387-397.
Mannuzzu, L. M., Maronne, M. M., and Isacoff, E. Y. (1996). Direct physical measure of conformational rearrangement underlying potassium channel gating. Science 271:213-216.
Noda, M., Shizimu, S., Tanabe, T., Takai, T., Kayano, T., Ikeda, T., Takahashi, H., Nakayama, H., Kanaoka, Y., and Minamino, N. (1984). Primary structure of Electrophorus electricus sodium channel deduced from cDNA sequence. Nature 321:121-127.
Rayner, M. D., Starkus, J. G., and Ruben, P. C. (1993). Hydration forces in ion channel gating. Commun. Mol. Cell. Biophys. 8(3):155-187.
Richmond, J. E., VanDeCarr, D., Featherstone, D. E., George, A. L., Jr., and Ruben, P. C. (1997). Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant. Biophys. J. 73:1896-1903.
Stuhmer, W., Conti, F., Suzuki, H., Wang, X., Noda, M., Yahagi, N., Kubo, H., and Numa, S. (1989). Structural parts involved in activation and inactivation of the sodium channel. Nature 339:597-604.
Yang, N., and Horn, R. (1995). Evidence for voltage-dependent S4 movement in sodium channels. Neuron 15:213-218.
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Groome, J.R., Fujimoto, E. & Ruben, P.C. The Delay in Recovery from Fast Inactivation in Skeletal Muscle Sodium Channels Is Deactivation. Cell Mol Neurobiol 20, 521–527 (2000). https://doi.org/10.1023/A:1007040731407
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DOI: https://doi.org/10.1023/A:1007040731407