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Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents
Brian W. Jarecki, … , James O. Jackson II, Theodore R. Cummins
Brian W. Jarecki, … , James O. Jackson II, Theodore R. Cummins
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):369-378. https://doi.org/10.1172/JCI40801.
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Research Article Article has an altmetric score of 6

Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents

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Abstract

Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat–derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.

Authors

Brian W. Jarecki, Andrew D. Piekarz, James O. Jackson II, Theodore R. Cummins

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Figure 3

Computer simulation of sodium conductances and DRG neuron excitability.

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Computer simulation of sodium conductances and DRG neuron excitability.
...
(A) Diagram of Markov models for VGSC conductances. An 8-state Markov model was used for simulation of VGSC conductances without resurgent currents. C1–C3, closed (nonconducting) states; O, open (conducting) state; I1–I4, inactivated (also nonconducting) states. A 9-state Markov model incorporated the resurgent current blocking factor. The OB state (boxed) represents channels blocked by this factor. (B) Simulated Nav1.7 (black trace) and Nav1.7-I1461T (red trace) currents elicited by a voltage step from –100 mV to +10 mV. (C) Simulated resurgent currents generated by model Nav1.7 (black trace) and Nav1.7-I1461T (red trace) conductances. Model currents were elicited with the standard resurgent current voltage protocol shown in Figure 2E. (D) In simulated DRG neurons with Nav1.7 channels, 70 pA depolarizing current is required to elicit an AP with or without resurgent current simulation. Conversely, only 40 pA is needed to elicit an AP in a simulated neuron with Nav1.7-I1461T channels, and a train of high-frequency APs is generated when the modeled Nav1.7-I1461T channels generate resurgent currents.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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