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Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons

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An Erratum to this article was published on 31 July 2012

Abstract

Injury to neural tissue renders voltage-gated Na+ (Nav) channels leaky. Even mild axonal trauma initiates Na+ -loading, leading to secondary Ca2+-loading and white matter degeneration. The nodal isoform is Nav1.6 and for Nav1.6-expressing HEK-cells, traumatic whole cell stretch causes an immediate tetrodotoxin-sensitive Na+-leak. In stretch-damaged oocyte patches, Nav1.6 current undergoes damage-intensity dependent hyperpolarizing- (left-) shifts, but whether left-shift underlies injured-axon Nav-leak is uncertain. Nav1.6 inactivation (availability) is kinetically limited by (coupled to) Nav activation, yielding coupled left-shift (CLS) of the two processes: CLS should move the steady-state Nav1.6 “window conductance” closer to typical firing thresholds. Here we simulated excitability and ion homeostasis in free-running nodes of Ranvier to assess if hallmark injured-axon behaviors—Na+-loading, ectopic excitation, propagation block—would occur with Nav-CLS. Intact/traumatized axolemma ratios were varied, and for some simulations Na/K pumps were included, with varied in/outside volumes. We simulated saltatory propagation with one mid-axon node variously traumatized. While dissipating the [Na+] gradient and hyperactivating the Na/K pump, Nav-CLS generated neuropathic pain-like ectopic bursts. Depending on CLS magnitude, fraction of Nav channels affected, and pump intensity, tonic or burst firing or nodal inexcitability occurred, with [Na+] and [K+] fluctuating. Severe CLS-induced inexcitability did not preclude Na+-loading; in fact, the steady-state Na+-leaks elicited large pump currents. At a mid-axon node, mild CLS perturbed normal anterograde propagation, and severe CLS blocked saltatory propagation. These results suggest that in damaged excitable cells, Nav-CLS could initiate cellular deterioration with attendant hyper- or hypo-excitability. Healthy-cell versions of Nav-CLS, however, could contribute to physiological rhythmic firing.

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Acknowledgements

We thank André Longtin and Na Yu for helpful discussions during the preparation of this manuscript. Our research was supported by funds from NSERC, HSF and CIHR.

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  1. Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario, K1N 6N5, Canada

    Pierre-Alexandre Boucher & Béla Joós

  2. Neurosciences, Ottawa Hospital Research Institute, Ottawa, Ontario, K1H8M5, Canada

    Catherine E. Morris

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  1. Pierre-Alexandre Boucher
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Boucher, PA., Joós, B. & Morris, C.E. Coupled left-shift of Nav channels: modeling the Na+-loading and dysfunctional excitability of damaged axons. J Comput Neurosci 33, 301–319 (2012). https://doi.org/10.1007/s10827-012-0387-7

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