A mutation in the pore of the sodium channel alters gating

Gordon F. Tomaselli, N. Chiamvimonvat, H. B. Nuss, J. R. Balser, M. T. Pérez-García, R. H. Xu, D. W. Orias, P. H. Backx, E. Marban

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Abstract

Ion permeation and channel gating are classically considered independent processes, but site-specific mutagenesis studies in K channels suggest that residues in or near the ion-selective pore of the channel can influence activation and inactivation. We describe a mutation in the pore of the skeletal muscle Na channel that alters gating. This mutation, I-W53C (residue 402 in the mu 1 sequence), decreases the sensitivity to block by tetrodotoxin and increases the sensitivity to block by externally applied Cd2+ relative to the wild-type channel, placing this residue within the pore near the external mouth. Based on contemporary models of the structure of the channel, this residue is remote from the regions of the channel known to be involved in gating, yet this mutation abbreviates the time to peak and accelerates the decay of the macroscopic Na current. At the single-channel level we observe a shortening of the latency to first opening and a reduction in the mean open time compared with the wild-type channel. The acceleration of macroscopic current kinetics in the mutant channels can be simulated by changing only the activation and deactivation rate constants while constraining the microscopic inactivation rate constants to the values used to fit the wild-type currents. We conclude that the tryptophan at position 53 in the domain IP-loop may act as a linchpin in the pore that limits the opening transition rate. This effect could reflect an interaction of I-W53 with the activation voltage sensors or a more global gating-induced change in pore structure.

Original languageEnglish (US)
Pages (from-to)1814-1827
Number of pages14
JournalBiophysical Journal
Volume68
Issue number5
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Sodium Channels
Mutation
Ion Channel Gating
Tetrodotoxin
Site-Directed Mutagenesis
Tryptophan
Mouth
Skeletal Muscle
Ions

ASJC Scopus subject areas

  • Biophysics

Cite this

Tomaselli, G. F., Chiamvimonvat, N., Nuss, H. B., Balser, J. R., Pérez-García, M. T., Xu, R. H., ... Marban, E. (1995). A mutation in the pore of the sodium channel alters gating. Biophysical Journal, 68(5), 1814-1827. https://doi.org/10.1016/S0006-3495(95)80358-9

A mutation in the pore of the sodium channel alters gating. / Tomaselli, Gordon F.; Chiamvimonvat, N.; Nuss, H. B.; Balser, J. R.; Pérez-García, M. T.; Xu, R. H.; Orias, D. W.; Backx, P. H.; Marban, E.

In: Biophysical Journal, Vol. 68, No. 5, 01.01.1995, p. 1814-1827.

Research output: Contribution to journalArticle

Tomaselli, GF, Chiamvimonvat, N, Nuss, HB, Balser, JR, Pérez-García, MT, Xu, RH, Orias, DW, Backx, PH & Marban, E 1995, 'A mutation in the pore of the sodium channel alters gating', Biophysical Journal, vol. 68, no. 5, pp. 1814-1827. https://doi.org/10.1016/S0006-3495(95)80358-9
Tomaselli GF, Chiamvimonvat N, Nuss HB, Balser JR, Pérez-García MT, Xu RH et al. A mutation in the pore of the sodium channel alters gating. Biophysical Journal. 1995 Jan 1;68(5):1814-1827. https://doi.org/10.1016/S0006-3495(95)80358-9
Tomaselli, Gordon F. ; Chiamvimonvat, N. ; Nuss, H. B. ; Balser, J. R. ; Pérez-García, M. T. ; Xu, R. H. ; Orias, D. W. ; Backx, P. H. ; Marban, E. / A mutation in the pore of the sodium channel alters gating. In: Biophysical Journal. 1995 ; Vol. 68, No. 5. pp. 1814-1827.
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