Boucher Pierre-Alexandre, Joós Béla, Morris Catherine E
Department of Physics, University of Ottawa, 150 Louis Pasteur, Ottawa, Ontario K1N 6N5, Canada.
J Comput Neurosci. 2012 Oct;33(2):301-19. doi: 10.1007/s10827-012-0387-7. Epub 2012 Apr 5.
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.
神经组织损伤会使电压门控性Na⁺（Nav）通道出现渗漏。即使是轻微的轴突损伤也会引发Na⁺内流，导致继发性Ca²⁺内流和白质变性。结区的亚型是Nav1.6，对于表达Nav1.6的HEK细胞，创伤性全细胞拉伸会导致立即出现河豚毒素敏感的Na⁺渗漏。在拉伸损伤的卵母细胞膜片上，Nav1.6电流会发生依赖于损伤强度的超极化（向左）移位，但这种左移是否是受损轴突Nav渗漏的基础尚不确定。Nav1.6失活（可用性）在动力学上受Nav激活（与之耦合）的限制，导致这两个过程的耦合左移（CLS）：CLS应使稳态Nav1.6“窗口电导”更接近典型的发放阈值。在这里，我们模拟了自由运行的郎飞结的兴奋性和离子稳态，以评估Nav-CLS是否会出现标志性的受损轴突行为——Na⁺内流、异位兴奋、传导阻滞。完整/受创伤的轴膜比例各不相同，在一些模拟中还包括了Na/K泵，细胞内外体积也各不相同。我们模拟了一个轴突中部节点受到不同程度创伤时的跳跃式传导。在耗散[Na⁺]梯度并使Na/K泵过度激活的同时，Nav-CLS产生了神经性疼痛样的异位爆发。根据CLS的大小、受影响的Nav通道比例和泵的强度，会出现强直性或爆发性发放或结区兴奋性丧失，[Na⁺]和[K⁺]会发生波动。严重的CLS诱导的兴奋性丧失并不排除Na⁺内流；事实上，稳态Na⁺渗漏会引发大量的泵电流。在轴突中部节点，轻度CLS会干扰正常的顺向传导，严重的CLS会阻断跳跃式传导。这些结果表明，在受损的可兴奋细胞中，Nav-CLS可能引发细胞恶化，并伴有过度或低兴奋性。然而，健康细胞版本的Nav-CLS可能有助于生理性节律发放。
