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首页> 外文期刊>Journal of Computational Neuroscience >Coupled left-shift of Nav channels: modeling the Na~+-loading and dysfunctional excitability of damaged axons
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Coupled left-shift of Nav channels: modeling the Na~+-loading and dysfunctional excitability of damaged axons

机译：Nav通道的左移耦合：模拟受损轴突的Na〜+负荷和功能异常的兴奋性

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Injury to neural tissue renders voltage-gated Na~+ (Nav) channels leaky. Even mild axonal trauma initiates Na~+-loading, leading to secondary Ca~(2+)-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, Navl.6 current undergoes damage-intensity dependent hyperpolarizing- (left-) shifts, but whether left-shift underlies injured-axon Nav-leak is uncertain. Navl.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 Navl.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 NaMoading; 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.
机译：对神经组织的损伤使电压门控的Na〜+（Nav）通道泄漏。即使是轻度的轴突损伤也会引发Na〜+负荷，导致继发的Ca〜（2+）负荷和白质变性。节点亚型为Nav1.6，对于表达Nav1.6的HEK细胞，创伤性全细胞牵张会引起河豚毒素敏感的Na〜+泄漏。在拉伸损伤的卵母细胞斑中，Nav1。6电流经历损伤强度依赖性的超极化-（左）移位，但是尚不清楚左移位是否是受伤的轴突Nav-泄漏的基础。 Navl6的失活（可用性）受到Nav激活的动力学限制（耦合），产生两个过程的耦合左移（CLS）：CLS应将稳态Navl.6“窗口电导”移近典型的发射阈值。在这里，我们在Ranvier的自由运行节点中模拟了兴奋性和离子稳态，以评估Nav-CLS是否会发生标志性的损伤轴突行为-Na〜+负荷，异位激发，传播阻滞。完整/创伤性腋窝动脉瘤的比率有所不同，对于某些模拟，还包括Na / K泵，其内外容积均不同。我们模拟了一个轴突中部受各种创伤的盐分繁殖。在消除[Na〜+]梯度并过度激活Na / K泵时，Nav-CLS产生了神经性疼痛样异位猝发。取决于CLS大小，受影响的Nav通道分数以及泵浦强度，补品或爆发性发射或节点不兴奋发生，其中[Na〜+]和[K〜+]波动。严重的CLS诱发的兴奋性并不能排除NaMoading。实际上，稳态Na〜+泄漏会引起大的泵浦电流。在轴突中部，轻度CLS干扰正常的顺行性繁殖，而严重的CLS阻止盐分繁殖。这些结果表明，在受损的兴奋性细胞中，Nav-CLS可能伴随着过度兴奋或刺激不足而引发细胞退化。但是，健康细胞版本的Nav-CLS可能有助于生理节律性放电。

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