ArticleThe Journal of general physiology2004
Block of inactivation-deficient Na+ channels by local anesthetics in stably transfected mammalian cells: evidence for drug binding along the activation pathway.
Article in The Journal of general physiology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- A sodium channel mutant removes fast inactivation with the inactivation particle bound.The Journal of general physiology · 2025Article
- Sodium Channels and Local Anesthetics-Old Friends With New Perspectives.Frontiers in pharmacology · 2022Review
- Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771.Molecular pharmacology · 2020Article
- Propofol inhibits prokaryotic voltage-gated NaThe Journal of general physiology · 2018Article
- Cardiac Na Channels: Structure to Function.Current topics in membranes · 2016Article
- Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins.Channels (Austin, Tex.) · 2016Article
- Reporting sodium channel activity using calcium flux: pharmacological promiscuity of cardiac Nav1.5.Molecular pharmacology · 2015Article
- Locating the route of entry and binding sites of benzocaine and phenytoin in a bacterial voltage gated sodium channel.PLoS computational biology · 2014Article
- Block of human cardiac sodium channels by lacosamide: evidence for slow drug binding along the activation pathway.Molecular pharmacology · 2014Article
- Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel.Nature communications · 2013Article
- The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity.The Journal of physiology · 2012Article
- State-Dependent Inhibition of Sodium Channels by Local Anesthetics: A 40-Year Evolution.Biochemistry (Moscow) Supplement. Series A, Membrane and cell biology · 2012Article
- Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances.Archives of toxicology · 2012Review
- Mechanisms of atrial-selective block of Na⁺ channels by ranolazine: II. Insights from a mathematical model.American journal of physiology. Heart and circulatory physiology · 2011Article
- The sodium channel as a target for local anesthetic drugs.Frontiers in pharmacology · 2011Article
- Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics.The Journal of general physiology · 2010Article
- Fast- or slow-inactivated state preference of Na+ channel inhibitors: a simulation and experimental study.PLoS computational biology · 2010Article
- State-Dependent Modification of Voltage-Gated Sodium Channels by Pyrethroids.Pesticide biochemistry and physiology · 2010Article
- State-dependent block of Na+ channels by articaine via the local anesthetic receptor.The Journal of membrane biology · 2009Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
According to the classic modulated receptor hypothesis, local anesthetics (LAs) such as benzocaine and lidocaine bind preferentially to fast-inactivated Na(+) channels with higher affinities. However, an alternative view suggests that activation of Na(+) channels plays a crucial role in promoting high-affinity LA binding and that fast inactivation per se is not a prerequisite for LA preferential binding. We investigated the role of activation in LA action in inactivation-deficient rat muscle Na(+) channels (rNav1.4-L435W/L437C/A438W) expressed in stably transfected Hek293 cells. The 50% inhibitory concentrations (IC(50)) for the open-channel block at +30 mV by lidocaine and benzocaine were 20.9 +/- 3.3 microM (n = 5) and 81.7 +/- 10.6 microM (n = 5), respectively; both were comparable to inactivated-channel affinities. In comparison, IC(50) values for resting-channel block at -140 mV were >12-fold higher than those for open-channel block. With 300 microM benzocaine, rapid time-dependent block (tau approximately 0.8 ms) of inactivation-deficient Na(+) currents occurred at +30 mV, but such a rapid time-dependent block was not evident at -30 mV. The peak current at -30 mV, however, was reduced more severely than that at +30 mV. This phenomenon suggested that the LA block of intermediate closed states took place notably when channel activation was slow. Such closed-channel block also readily accounted for the LA-induced hyperpolarizing shift in the conventional steady-state inactivation measurement. Our data together illustrate that the Na(+) channel activation pathway, including most, if not all, transient intermediate closed states and the final open state, promotes high-affinity LA binding.
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