Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.
Immune or Genetic-Mediated Disruption of CASPR2 Causes Pain Hypersensitivity Due to Enhanced Primary Afferent Excitability.
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DOI：
10.1016/j.neuron.2018.01.033
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发表时间：
2018-02-21
期刊：
影响因子：
16.2
通讯作者：
Bennett DL
中科院分区：
文献类型：
--
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
人类抗接触素相关蛋白样蛋白2(CASPR2)的自身抗体经常与神经病理性疼痛有关，CASPR2突变已被认为与自闭症谱系障碍有关，在自闭症谱系障碍中，感觉功能障碍日益被认识。当人CASPR2自身抗体注射到小鼠体内时，会受到外围限制，并导致在没有神经损伤的情况下出现机械性疼痛相关超敏反应。因此，我们研究了CASPR2调节伤害性感受功能的机制。缺乏CASPR2(cntnap2−/−)的小鼠表现出对有害机械刺激、热和变应原的疼痛相关超敏反应增强。在cntnap2−/−小鼠中，初级传入兴奋性和随后的背角内伤害性传递均增加。免疫或遗传消融CASPR2通过调节胞体膜上KV1通道的表达，以细胞自主的方式增强DRG神经元的兴奋性。这是第一个被动转移自身免疫性周围神经病理性疼痛障碍的例子，表明CASPR2在调节细胞内背根神经节(DRG)神经元的兴奋性方面具有关键作用。用人CASPR2-Abs治疗引起小鼠机械超敏反应CASPR2-Abs保持PNS限制并增强疼痛行为而无神经损伤cntnap2−/−小鼠(缺乏全长CASPR2)CASPR2通过KV1通道转运到膜Dawes等人调节背根神经节细胞的兴奋性。研究表明，CASPR2是自身免疫性疼痛障碍的靶点，通过调节初级传入兴奋性来调节感觉功能。抗CASPR2的人自身抗体可引起疼痛相关的超敏反应，并通过降低KV1通道功能增强DRG细胞的兴奋性。
Human autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability. Treatment with human CASPR2-Abs causes mechanical hypersensitivity in mice CASPR2-Abs remain PNS restricted and enhance pain behavior without neural injury Pain behavior is increased in Cntnap2−/− mice (lacking full-length CASPR2) CASPR2 regulates DRG cell excitability via Kv1 channel trafficking to the membrane Dawes et al. show that CASPR2, the target of an autoimmune pain disorder, regulates sensory function through tuning of primary afferent excitability. Human autoantibodies to CASPR2 cause pain-related hypersensitivity and enhance DRG cell excitability through reduced Kv1 channel function.
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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：
7.3
作者：
Ludwig RJ;Vanhoorelbeke K;Leypoldt F;Kaya Z;Bieber K;McLachlan SM;Komorowski L;Luo J;Cabral-Marques O;Hammers CM;Lindstrom JM;Lamprecht P;Fischer A;Riemekasten G;Tersteeg C;Sondermann P;Rapoport B;Wandinger KP;Probst C;El Beidaq A;Schmidt E;Verkman A;Manz RA;Nimmerjahn F
通讯作者：
Nimmerjahn F
影响因子：
16.2
作者：
Arcourt, Alice;Gorham, Louise;Lechner, Stefan G.
通讯作者：
Lechner, Stefan G.
影响因子：
5.3
作者：
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通讯作者：
Viana, Felix
影响因子：
2.5
作者：
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通讯作者：
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