title: Coupled left-shift of Nav channels: modeling the Na⁺-loading and dysfunctional excitability of damaged axons.
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.
authors.affiliation: Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario K1N 6N5, Canada.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Boucher
authors.forename: Béla
authors.initials: B
authors.lastname: Joós
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Morris
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001703:Biophysics; D003198:Computer Simulation / Q000706:statistics & numerical data; D020833:Diffuse Axonal Injury / Q000473:pathology*; D004558:Electric Stimulation; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008954:Models, Biological; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009431:Neural Conduction / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020033:Protein Isoforms; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D015222:Sodium Channels; D012964:Sodium; D000251:Adenosine Triphosphatases