Mechanistic link between lidocaine block and inactivation probed by outer pore mutations in the rat μ1 skeletal muscle sodium channel
| Autor: | Laura A. Hastings, Svetlana Z. Stepanovic, Gordon F. Tomaselli, Eduardo Marbán, Nicholas G. Kambouris, Jeffrey R. Balser |
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| Rok vydání: | 1998 |
| Předmět: |
Patch-Clamp Techniques
Lidocaine Physiology Allosteric regulation Xenopus Sodium Channels Membrane Potentials Xenopus laevis Sodium channel blocker medicine Animals Patch clamp Muscle Skeletal biology Chemistry Sodium channel Skeletal muscle Original Articles Hyperpolarization (biology) biology.organism_classification Electric Stimulation Rats Electrophysiology Kinetics medicine.anatomical_structure Biochemistry Mutation Mutagenesis Site-Directed Oocytes Biophysics Sodium Channel Blockers medicine.drug |
| Zdroj: | The Journal of Physiology. 512:693-705 |
| ISSN: | 0022-3751 |
| DOI: | 10.1111/j.1469-7793.1998.693bd.x |
| Popis: | 1. Mutations that disrupt Na+ channel fast inactivation attenuate lidocaine (lignocaine)-induced use dependence; however, the pharmacological role of slower inactivation processes remains unclear. In Xenopus oocytes, tryptophan substitution in the outer pore of the rat skeletal muscle channel (micro1-W402) alters partitioning among fast- and slow-inactivated states. We therefore examined the effects of W402 mutations on lidocaine block. 2. Recovery from inactivation exhibited three kinetic components (IF, fast; IM, intermediate; IS, slow). The effects of W402A and W402S on IF and IS differed, but both mutants (with or without beta1 subunit coexpression) decreased the amplitude of IM. In wild-type channels, lidocaine imposed a delayed recovery component with intermediate kinetics, and use-dependent block was attenuated in both W402A and W402S. 3. To examine the pharmacological role of IS relative to IM, drug-exposed beta1-coexpressed channels were subjected to 2 min depolarizations. Lidocaine had no effect on sodium current (INa) after a 1 s hyperpolarization interval that allowed recovery from IM but not IS, suggesting that lidocaine affinity for IS is low. 4. Both W402 mutations reduced occupancy of IM in drug-free conditions, and also induced resistance to use-dependent block. We propose that lidocaine-induced use dependence may involve an allosteric conformational change in the outer pore. |
| Databáze: | OpenAIRE |
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