Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders.
Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders.
复制标题
DOI：
10.1186/1744-8069-6-24
复制
发表时间：
2010-04-29
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：
Cheng X;Dib-Hajj SD;Tyrrell L;Wright DA;Fischer TZ;Waxman SG
在背根神经节（DRG）神经元中表达的钠通道NaV1.7中的两组功能获得性突变产生两种临床上不同的疼痛综合征-遗传性红斑性肢痛症（IEM）和阵发性极度疼痛障碍（PEPD）。IEM的特征在于足部或手部的间歇性烧灼痛和皮肤发红，由温暖或轻度运动触发，而PEPD的特征在于直肠、眼部和下颌疼痛发作，伴有皮肤潮红，由排便和肛周刺激触发。大多数IEM突变位于通道结构域I和II内，而大多数PEPD突变位于结构域III和IV内。结构上的二分法平行的生物物理效应的两种类型的突变，IEM突变转移电压依赖性的NaV1.7激活在超极化方向，和PEPD突变转移快速失活的NaV1.7在去极化方向。虽然四个IEM和四个PEPD突变位于不同结构域（IEM：结构域I和II; PEPD：结构域III和IV）中连接区段4和5的细胞质接头（S4-S5接头）内，但迄今为止还没有报道S4-S5接头容纳IEM和PEPD突变。我们已经在NaV1.7的DIII/S4-S5接头的C-末端内鉴定了新的IEM突变P1308 L，其距离位于该接头的N-末端内的已知PEPD突变V1298 F十个氨基酸。我们用电压钳比较了两种突变通道的生物物理特性，用电流钳研究了它们对DRG神经元兴奋性的影响。我们确认P1308 L和V1298 F分别表现为原型IEM和PEPD突变。我们还表明，表达P1308 L或V1298 F的DRG神经元变得过度兴奋，相比表达野生型通道的DRG神经元。我们的结果为DIII/S4-S5接头N末端和C末端在通道失活和激活中的不同作用提供了证据，并证明了携带这些突变的患者疼痛的细胞基础。
Two groups of gain-of-function mutations in sodium channel NaV1.7, which are expressed in dorsal root ganglion (DRG) neurons, produce two clinically-distinct pain syndromes - inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is characterized by intermittent burning pain and skin redness in the feet or hands, triggered by warmth or mild exercise, while PEPD is characterized by episodes of rectal, ocular and mandibular pain accompanied with skin flushing, triggered by bowel movement and perianal stimulation. Most of the IEM mutations are located within channel domains I and II, while most of the PEPD mutations are located within domains III and IV. The structural dichotomy parallels the biophysical effects of the two types of mutations, with IEM mutations shifting voltage-dependence of NaV1.7 activation in a hyperpolarized direction, and PEPD mutations shifting fast-inactivation of NaV1.7 in a depolarized direction. While four IEM and four PEPD mutations are located within cytoplasmic linkers joining segments 4 and 5 (S4-S5 linkers) in the different domains (IEM: domains I and II; PEPD: domains III and IV), no S4-S5 linker has been reported to house both IEM and PEPD mutations thus far. We have identified a new IEM mutation P1308L within the C-terminus of the DIII/S4-S5 linker of NaV1.7, ten amino acids from a known PEPD mutation V1298F which is located within the N-terminus of this linker. We used voltage-clamp to compare the biophysical properties of the two mutant channels and current-clamp to study their effects on DRG neuron excitability. We confirm that P1308L and V1298F behave as prototypical IEM and PEPD mutations, respectively. We also show that DRG neurons expressing either P1308L or V1298F become hyperexcitable, compared to DRG neurons expressing wild-type channels. Our results provide evidence for differential roles of the DIII/S4-S5 linker N- and C-termini in channel inactivation and activation, and demonstrate the cellular basis for pain in patients carrying these mutations.
登录
查看更多内容
影响因子：
3.3
作者：
Cheng, Xiaoyang;Dib-Hajj, Sulayman D.;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
5.3
作者：
Choi, Jin-Sung;Zhang, Lili;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
11.2
作者：
Han, CY;Rush, AM;Waxman, SG
通讯作者：
Waxman, SG
影响因子：
14.8
作者：
Dib-Hajj, Sulayman D.;Choi, Jin Sung;Waxman, Stephen G.
通讯作者：
Waxman, Stephen G.
影响因子：
64.8
作者：
Jiang, YX;Lee, A;MacKinnon, R
通讯作者：
MacKinnon, R