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Molecular Action of Lidocaine on the Voltage Sensors of Sodium Channels
| Content Provider | Scilit |
|---|---|
| Author | Sheets, Michael F. Hanck, Dorothy A. |
| Copyright Year | 2003 |
| Description | Block of sodium ionic current by lidocaine is associated with alteration of the gating charge-voltage (Q-V) relationship characterized by a 38% reduction in maximal gating charge $(Q_{max}$) and by the appearance of additional gating charge at negative test potentials. We investigated the molecular basis of the lidocaine-induced reduction in cardiac Na channel–gating charge by sequentially neutralizing basic residues in each of the voltage sensors (S4 segments) in the four domains of the human heart Na channel (hH1a). By determining the relative reduction in the $Q_{max}$ of each mutant channel modified by lidocaine we identified those S4 segments that contributed to a reduction in gating charge. No interaction of lidocaine was found with the voltage sensors in domains I or II. The largest inhibition of charge movement was found for the S4 of domain III consistent with lidocaine completely inhibiting its movement. Protection experiments with intracellular MTSET (a charged sulfhydryl reagent) in a Na channel with the fourth outermost arginine in the S4 of domain III mutated to a cysteine demonstrated that lidocaine stabilized the S4 in domain III in a depolarized configuration. Lidocaine also partially inhibited movement of the S4 in domain IV, but lidocaine9s most dramatic effect was to alter the voltage-dependent charge movement of the S4 in domain IV such that it accounted for the appearance of additional gating charge at potentials near −100 mV. These findings suggest that lidocaine9s actions on Na channel gating charge result from allosteric coupling of the binding site(s) of lidocaine to the voltage sensors formed by the S4 segments in domains III and IV. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2217326/pdf http://jgp.rupress.org/content/121/2/163.full.pdf |
| Ending Page | 175 |
| Page Count | 13 |
| Starting Page | 163 |
| DOI | 10.1085/jgp.20028651 |
| Journal | The Journal of general physiology |
| Issue Number | 2 |
| Volume Number | 121 |
| Language | English |
| Publisher | Rockefeller University Press |
| Publisher Date | 2003-02-01 |
| Access Restriction | Open |
| Subject Keyword | Biophysics Gating Current Nav1.5 Heart Mutant Local Anesthetic Drug Journal: The Journal of general physiology (Vol- 121, Issue- 2) |
| Content Type | Text |
