Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable.
Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable.
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DOI：
10.1186/1744-8069-4-37
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发表时间：
2008-09-19
期刊：
影响因子：
3.3
通讯作者：
Waxman SG
中科院分区：
文献类型：
--
作者：
Dib-Hajj SD;Estacion M;Jarecki BW;Tyrrell L;Fischer TZ;Lawden M;Cummins TR;Waxman SG
阵发性极度疼痛障碍（PEPD）是一种常染色体显性疼痛性神经病，许多（但不是全部）病例与编码电压门控钠通道Nav1.7的SCN9A的功能获得性突变有关。剧烈疼痛发作和皮肤潮红始于婴儿期，由肛周探查或排便引起，随着年龄的增长，疼痛进展至眼部和下颌区域。卡马西平可以有效缓解症状，而其他药物，包括其他抗癫痫药的效果较差。对来自一名被诊断患有PEPD的英国患者的SCN 9A编码外显子进行测序，已经确定了在结构域IV中连接区段S4和S5的接头中的甲硫氨酸1627至赖氨酸（M1627K）取代。我们证实，M1627 K去极化的电压依赖性的快速失活，而基本上不改变激活或缓慢失活，从开放状态与较慢的动力学失活。我们在这里表明，M1627 K不改变发展的封闭状态失活，和M1627 K通道从快速失活恢复速度比野生型通道，并产生更大的电流响应于一个缓慢的斜坡刺激。使用电流钳记录，我们还表明，M1627K突变通道降低了DRG神经元的单个动作电位的阈值，并增加了响应于分级刺激的动作电位的数量。1627 K突变以前被确定在一个散发的情况下，PEPD从法国，我们现在报告在一个英国家庭。我们证实了突变体M1627K对Nav1.7快速失活的影响的初步表征，并将分析扩展到通道的其他门控特性。我们还表明，M1627K突变通道使DRG神经元过度兴奋。我们的新数据提供了改变通道生物物理学和PEPD患者疼痛之间的联系。
Paroxysmal extreme pain disorder (PEPD) is an autosomal dominant painful neuropathy with many, but not all, cases linked to gain-of-function mutations in SCN9A which encodes voltage-gated sodium channel Nav1.7. Severe pain episodes and skin flushing start in infancy and are induced by perianal probing or bowl movement, and pain progresses to ocular and mandibular areas with age. Carbamazepine has been effective in relieving symptoms, while other drugs including other anti-epileptics are less effective. Sequencing of SCN9A coding exons from an English patient, diagnosed with PEPD, has identified a methionine 1627 to lysine (M1627K) substitution in the linker joining segments S4 and S5 in domain IV. We confirm that M1627K depolarizes the voltage-dependence of fast-inactivation without substantially altering activation or slow-inactivation, and inactivates from the open state with slower kinetics. We show here that M1627K does not alter development of closed-state inactivation, and that M1627K channels recover from fast-inactivation faster than wild type channels, and produce larger currents in response to a slow ramp stimulus. Using current-clamp recordings, we also show that the M1627K mutant channel reduces the threshold for single action potentials in DRG neurons and increases the number of action potentials in response to graded stimuli. M1627K mutation was previously identified in a sporadic case of PEPD from France, and we now report it in an English family. We confirm the initial characterization of mutant M1627K effect on fast-inactivation of Nav1.7 and extend the analysis to other gating properties of the channel. We also show that M1627K mutant channels render DRG neurons hyperexcitable. Our new data provide a link between altered channel biophysics and pain in PEPD patients.
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影响因子：
6.5
作者：
Drenth, JPH;te Morsche, RHM;Jansen, JBMJ
通讯作者：
Jansen, JBMJ
影响因子：
3.3
作者：
Cheng, Xiaoyang;Dib-Hajj, Sulayman D.;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
DOI：
10.1016/s0169-328x(96)00241-0
发表时间：
1997-04-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Felts, PA;Yokoyama, S;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
11.2
作者：
Han, CY;Rush, AM;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
4.8
作者：
Kellenberger, S;Scheuer, T;Catterall, WA
通讯作者：
Catterall, WA