ABSTRACT

The voltage-gated sodium channel Na_v1.8 mediates the tetrodotoxin-resistant (TTX-R) Na⁺ current in nociceptive primary sensory neurons, which has an important role in the transmission of painful stimuli. Here, we describe the functional modulation of the human Na_v1.8 α-subunit in Xenopus oocytes by auxiliary β subunits. We found that the β3 subunit down-regulated the maximal Na⁺ current amplitude and decelerated recovery from inactivation of hNa_v1.8, whereas the β1 and β2 subunits had no such effects. The specific regulation of Na_v1.8 by the β3 subunit constitutes a potential novel regulatory mechanism of the TTX-R Na⁺ current in primary sensory neurons with potential implications in chronic pain states. In particular, neuropathic pain states are characterized by a down-regulation of Na_v1.8 accompanied by increased expression of the β3 subunit. Our results suggest that these two phenomena may be correlated, and that increased levels of the β3 subunit may directly contribute to the down-regulation of Na_v1.8. To determine which domain of the β3 subunit is responsible for the specific regulation of hNa_v1.8, we created chimeras of the β1 and β3 subunits and co-expressed them with the hNa_v1.8 α-subunit in Xenopus oocytes. The intracellular domain of the β3 subunit was shown to be responsible for the down-regulation of maximal Na_v1.8 current amplitudes. In contrast, the extracellular domain mediated the effect of the β3 subunit on hNa_v1.8 recovery kinetics.

摘要

电压门控钠通道 Na _v 1.8 介导伤害性初级感觉神经元中的河豚毒素抗性 (TTX-R) Na ⁺电流，这在疼痛刺激的传递中具有重要作用。在这里，我们描述了辅助 β 亚基对非洲爪蟾卵母细胞中人类 Na _v 1.8 α 亚基的功能调节。我们发现 β3 亚基下调了最大 Na ⁺电流幅度并减缓了 hNa _v 1.8失活的恢复，而 β1 和 β2 亚基没有这种影响。β3 亚基对 Na _v 1.8的特异性调控构成了 TTX-R Na ⁺的潜在新型调控机制初级感觉神经元中的电流对慢性疼痛状态具有潜在影响。特别是，神经性疼痛状态的特征是 Na _v 1.8 的下调伴随着 β3 亚基的表达增加。我们的结果表明这两种现象可能是相关的，β3 亚基水平的增加可能直接导致 Na _v 1.8的下调。为了确定 β3 亚基的哪个域负责 hNa _v 1.8的特定调控，我们创建了 β1 和 β3 亚基的嵌合体，并将它们与非洲爪蟾中的 hNa _v 1.8 α 亚基共表达卵母细胞。显示 β3 亚基的细胞内结构域负责最大 Na _v 1.8 电流幅度的下调。相比之下，细胞外结构域介导了 β3 亚基对 hNa _v 1.8 恢复动力学的影响。