Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
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DOI：
10.1093/brain/awab482
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发表时间：
2022-10-21
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电压门控钠通道Nav1.7双等位基因功能突变的患者表现为先天性疼痛不敏感(CIP)，而据报道低阈值机械感觉是正常的。应用心理物理学方法(6例CIP患者和86例健康对照)和面部肌电检查(3例CIP患者和8例健康对照)，我们发现这些患者的情感触摸编码也存在异常，这种异常是由特殊传入C-低阈值机械感受器(C-LTMR)介导的。在小鼠中，我们发现C-LTMR表达高水平的Nav1.7。在C-LTMR中，Nav1.7的遗传缺失或选择性药物抑制导致总钠电流密度显著降低，机械阈值增加，对非伤害性冷却的敏感性降低。在小鼠的C-LTMR中，失去Nav1.7的行为后果是von Frey机械阈值升高，对温度梯度的降温敏感性降低。因此，Nav1.7不仅对正常的疼痛感知至关重要，而且对正常的C-LTMR功能、冷敏和情感触摸也是必不可少的。Middleton，Perini等人。表明Nav1.7的作用超越了疼痛感知。使用多学科、跨物种的方法，他们表明，Nav1.7对于小鼠和人类的C-低阈值机械感受器功能也是必不可少的，它调节愉悦的触摸、点状辨别和对冷却的敏感性。
Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch. Middleton, Perini et al. show that the role of Nav1.7 extends beyond pain perception. Using a multidisciplinary, cross-species approach, they show that Nav1.7 is also essential for C-low threshold mechanoreceptor function in mice and humans, regulating pleasant touch, punctate discrimination and sensitivity to cooling.
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影响因子：
64.5
作者：
Li L;Rutlin M;Abraira VE;Cassidy C;Kus L;Gong S;Jankowski MP;Luo W;Heintz N;Koerber HR;Woodbury CJ;Ginty DD
通讯作者：
Ginty DD
影响因子：
16.2
作者：
Dawes JM;Weir GA;Middleton SJ;Patel R;Chisholm KI;Pettingill P;Peck LJ;Sheridan J;Shakir A;Jacobson L;Gutierrez-Mecinas M;Galino J;Walcher J;Kühnemund J;Kuehn H;Sanna MD;Lang B;Clark AJ;Themistocleous AC;Iwagaki N;West SJ;Werynska K;Carroll L;Trendafilova T;Menassa DA;Giannoccaro MP;Coutinho E;Cervellini I;Tewari D;Buckley C;Leite MI;Wildner H;Zeilhofer HU;Peles E;Todd AJ;McMahon SB;Dickenson AH;Lewin GR;Vincent A;Bennett DL
通讯作者：
Bennett DL
影响因子：
7.4
作者：
Blesneac I;Themistocleous AC;Fratter C;Conrad LJ;Ramirez JD;Cox JJ;Tesfaye S;Shillo PR;Rice ASC;Tucker SJ;Bennett DLH
通讯作者：
Bennett DLH
影响因子：
11.2
作者：
Faber, Catharina G.;Hoeijmakers, Janneke G. J.;Merkies, Ingemar S. J.
通讯作者：
Merkies, Ingemar S. J.
影响因子：
8.8
作者：
Kupari, Jussi;Haring, Martin;Ernfors, Patrik
通讯作者：
Ernfors, Patrik