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- Title
Coupled left-shift of Nav channels: modeling the Na-loading and dysfunctional excitability of damaged axons.
- Authors
Boucher, Pierre-Alexandre; Joós, Béla; Morris, Catherine
- Abstract
Injury to neural tissue renders voltage-gated Na (Nav) channels leaky. Even mild axonal trauma initiates Na -loading, leading to secondary Ca-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.
- Subjects
SODIUM channels; AXONS; EXCITATION (Physiology); NEUROBIOLOGY; TETRODOTOXIN; NODES of Ranvier; SODIUM/POTASSIUM ATPase; ARRHYTHMIA
- Publication
Journal of Computational Neuroscience, 2012, Vol 33, Issue 2, p301
- ISSN
0929-5313
- Publication type
Article
- DOI
10.1007/s10827-012-0387-7