Depolarizing Nav and Hyperpolarizing Kv Channels Are Co-Trafficked in Sensory Neurons
Depolarizing Nav and Hyperpolarizing Kv Channels Are Co-Trafficked in Sensory Neurons
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DOI：
10.1523/jneurosci.0058-22.2022
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发表时间：
2022-06-15
影响因子：
5.3
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
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作者：
Higerd-Rusli, Grant P.;Alsaloum, Matthew;Waxman, Stephen G.
神经元的兴奋性依赖于不同功能通道的协调作用。电压门控钠（Na-v）和钾（K-v）通道在激发动作电位中具有不同但互补的作用：Na-v通道提供去极化电流，而K（v）通道提供超极化电流。多个Nay和K（v）通道的突变和功能障碍是兴奋性障碍的基础，包括疼痛和癫痫。调节离子通道运输可能为这些疾病提供潜在的治疗策略。然而，一个基本的问题是，这些具有不同功能作用的通道是独立运输的，还是一起包装在感觉轴突的相同囊泡中。我们已经使用光学脉冲追踪轴突长距离成像来研究Nay和K-v通道以及活的啮齿动物感觉神经元（来自雄性和雌性大鼠）中不同功能类别的其他轴突蛋白的运输。我们发现，类似于Na（v）1.7通道，Na（v）1.8和K（v）7.2通道在Rab 6a阳性囊泡中转运，并且在健康成熟的感觉神经元中表达的每种Na v通道亚型（Na（v）1.6，Na（v）1.7，Na（v）1.8和Na（v）1.9）在相同的囊泡中共同转运。此外，我们发现，多个轴突膜蛋白具有不同的生理功能（Na（V）1.7，K（V）7.2，和TNFR 1）在相同的囊泡cotransferred。然而，轴突膜蛋白的囊泡包装不是不加选择的，因为另一种轴突膜蛋白（NCX 2）在单独的囊泡中转运。这些结果为感觉神经元膜的发育和组织提供了新的线索，揭示了具有不同生理功能的轴突蛋白质复杂的分选到特定的运输囊泡中。
Neuronal excitability relies on coordinated action of functionally distinction channels. Voltage-gated sodium (Na-v) and potassium (K-v) channels have distinct but complementary roles in firing action potentials: Na-v channels provide depolarizing current while K(v )channels provide hyperpolarizing current. Mutations and dysfunction of multiple Nay and K(v )channels underlie disorders of excitability, including pain and epilepsy. Modulating ion channel trafficking may offer a potential therapeutic strategy for these diseases. A fundamental question, however, is whether these channels with distinct functional roles are transported independently or packaged together in the same vesicles in sensory axons. We have used Optical Pulse-Chase Axonal Long-distance imaging to investigate trafficking of Nay and K-v channels and other axonal proteins from distinct functional classes in live rodent sensory neurons (from male and female rats). We show that, similar to Na(v)1.7 channels, Na(v)1.8 and K(v)7.2 channels are transported in Rab6a-positive vesicles, and that each of the Na v channel isoforms expressed in healthy, mature sensory neurons (Na(v)1.6, Na(v)1.7, Na(v)1.8, and Na(v)1.9) is cotransported in the same vesicles. Further, we show that multiple axonal membrane proteins with different physiological functions (Na(v)1.7, K(v)7.2, and TNFR1) are cotransported in the same vesicles. However, vesicular packaging of axonal membrane proteins is not indiscriminate, since another axonal membrane protein (NCX2) is transported in separate vesicles. These results shed new light on the development and organization of sensory neuron membranes, revealing complex sorting of axonal proteins with diverse physiological functions into specific transport vesicles.