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State-Dependent Block of Na+ Channels by Articaine Via the Local Anesthetic Receptor

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Abstract

Articaine is widely used as a local anesthetic (LA) in dentistry, but little is known regarding its blocking actions on Na+ channels. We therefore examined the state-dependent block of articaine first in rat skeletal muscle rNav1.4 Na+ channels expressed in Hek293t cells. Articaine exhibited a weak block of resting rNav1.4 Na+ channels at −140 mV with a 50% inhibitory concentration (IC50) of 378 ± 26 μM (n = 5). The affinity was higher for inactivated Na+ channels measured at −70 mV with an IC50 value of 40.6 ± 2.7 μM (n = 5). The open-channel block by articaine was measured using inactivation-deficient rNav1.4 Na+ channels with an IC50 value of 15.8 ± 1.5 μM (n = 5). Receptor mapping demonstrated that articaine interacted strongly with a D4S6 phenylalanine residue, which is known to form a part of the LA receptor. Thus the block of rNav1.4 Na+ channels by articaine is via the conserved LA receptor in a highly state-dependent manner, with a ranking order of open (23.9×) > inactivated (9.3×) > resting (1×) state. Finally, the open-channel block by articaine was likewise measured in inactivation-deficient hNav1.7 and rNav1.8 Na+ channels, with IC50 values of 8.8 ± 0.1 and 22.0 ± 0.5 μM, respectively (n = 5), indicating that the high-affinity open-channel block by articaine is indeed preserved in neuronal Na+ channel isoforms.

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Acknowledgments

This work was supported by National Institutes of Health Grant GM48090. We are grateful to Dr. Edward Moczydlowski for the HEK293 cell line expressing wild-type rNav1.4 channels and to Drs. James Trimmer, Norbert Klugbauer, and John Wood for the rNav1.4, hNav1.7, and rNav1.8 cDNA clones, respectively.

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Authors and Affiliations

  1. Department of Anesthesia, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Ging Kuo Wang & Joanna Calderon

  2. Department of Pediatric Dentistry, School of Dental Medicine, Tufts University, 1 Kneeland Street, Boston, MA, 02111, USA

    Shiow-Jiin Jaw

  3. Department of Biology, State University of New York at Albany, Albany, NY, 12222, USA

    Sho-Ya Wang

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  1. Ging Kuo Wang
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  2. Joanna Calderon
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  3. Shiow-Jiin Jaw
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Correspondence to Shiow-Jiin Jaw.

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Wang, G.K., Calderon, J., Jaw, SJ. et al. State-Dependent Block of Na+ Channels by Articaine Via the Local Anesthetic Receptor. J Membrane Biol 229, 1–9 (2009). https://doi.org/10.1007/s00232-009-9170-8

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  • DOI: https://doi.org/10.1007/s00232-009-9170-8

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