NaV1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn.
NaV1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn.
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NaV1.7 mRNA 和蛋白质在人脊髓背角的假定投射神经元中的表达。
DOI：
10.1101/2023.02.04.527110
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Price,TheodoreJ
中科院分区：
文献类型：
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作者：
Shiers,Stephanie;Funk,Geoffrey;Cervantes,Anna;Horton,Peter;Dussor,Gregory;Hennen,Stephanie;Price,TheodoreJ
NaV1.7 是一种膜结合电压门控钠通道，优先沿初级感觉神经元表达，包括其周围和中枢神经末梢、轴突和背根神经节内的胞体，在放大膜去极化和疼痛神经传递中发挥着不可或缺的作用。编码 NaV1.7、SCN9A 的基因中的功能丧失和功能获得突变分别与人类痛觉完全丧失或疼痛加剧有关。作为人类基因验证支持的诱人疼痛靶点，许多化合物已被开发用于抑制 NaV1.7，但在临床试验中却令人失望。根本原因尚不清楚，但最近的报告表明，抑制伤害感受器传入神经末梢的 NaV1.7 对于通过药物抑制 NaV1.7 实现疼痛缓解至关重要。我们首次报道 NaV1.7 mRNA 在人脊髓背角的假定投射神经元 (NK1R+) 中表达，主要在第 1 和 2 层，以及深背角神经元和腹角运动神经元中。 NaV1.7 蛋白在终止于第 1-2 层的感觉神经元的中央轴突中发现，但也在常驻脊髓背角神经元的轴突初始段和进入前连合的轴突中检测到。鉴于投射神经元对于将伤害性信息从背角传递到大脑至关重要，这些数据支持背角 NaV1.7 表达可能在具有 SCN9A 基因突变的人类中观察到的疼痛表型以及在临床试验中实现镇痛功效方面发挥着未被重视的作用。
NaV1.7, a membrane-bound voltage-gated sodium channel, is preferentially expressed along primary sensory neurons, including their peripheral & central nerve endings, axons, and soma within the dorsal root ganglia and plays an integral role in amplifying membrane depolarization and pain neurotransmission. Loss- and gain-of-function mutations in the gene encoding NaV1.7, SCN9A, are associated with a complete loss of pain sensation or exacerbated pain in humans, respectively. As an enticing pain target supported by human genetic validation, many compounds have been developed to inhibit NaV1.7 but have disappointed in clinical trials. The underlying reasons are still unclear, but recent reports suggest that inhibiting NaV1.7 in central terminals of nociceptor afferents is critical for achieving pain relief by pharmacological inhibition of NaV1.7. We report for the first time that NaV1.7 mRNA is expressed in putative projection neurons (NK1R+) in the human spinal dorsal horn, predominantly in lamina 1 and 2, as well as in deep dorsal horn neurons and motor neurons in the ventral horn. NaV1.7 protein was found in the central axons of sensory neurons terminating in lamina 1–2, but also was detected in the axon initial segment of resident spinal dorsal horn neurons and in axons entering the anterior commissure. Given that projection neurons are critical for conveying nociceptive information from the dorsal horn to the brain, these data support that dorsal horn NaV1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations, and in achieving analgesic efficacy in clinical trials.