A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels.
A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels.
复制标题
DOI：
10.1186/s13041-020-00725-y
复制
发表时间：
2021-01-07
期刊：
影响因子：
3.6
通讯作者：
Zamponi GW
中科院分区：
文献类型：
--
作者：
Gambeta E;Gandini MA;Souza IA;Ferron L;Zamponi GW
在三叉神经痛患者中发现了一种新的错义突变CACNA 1A基因，该基因编码CaV2.1电压门控钙通道的孔形成α1亚基。该突变导致通道远端C-末端区域的脯氨酸2455被组氨酸（P2455 H）取代。由于该通道在神经递质释放中的良好表征作用，我们的目的是表征异源表达CaV2.1通道中P2455 H变体的生物物理特性。全细胞膜片钳记录野生型和突变体CaV2.1通道在tsA-201细胞中表达揭示，突变介导的去极化转变的电压依赖性的激活和失活。此外，P2455 H突变体强烈降低了通道的钙依赖性失活，这与功能的总体增益一致。因此，P2455 H CaV2.1错义突变改变了通道的门控特性，表明三叉神经系统中CaV2.1依赖性突触通讯的相关变化可能有助于三叉神经痛的发展。
A novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.
登录
查看更多内容
影响因子：
2.7
作者：
Ben-Johny M;Dick IE;Sang L;Limpitikul WB;Kang PW;Niu J;Banerjee R;Yang W;Babich JS;Issa JB;Lee SR;Namkung H;Li J;Zhang M;Yang PS;Bazzazi H;Adams PJ;Joshi-Mukherjee R;Yue DN;Yue DT
通讯作者：
Yue DT
影响因子：
4.9
作者：
Silberstein, SD
通讯作者：
Silberstein, SD
影响因子：
16.2
作者：
van den Maagdenberg, AMJM;Pietrobon, D;Ferrari, MD
通讯作者：
Ferrari, MD
影响因子：
4.9
作者：
Di Stefano, Giulia;Yuan, Jun-Hui;Truini, Andrea
通讯作者：
Truini, Andrea
影响因子：
3.3
作者：
Adams, Paul J.;Garcia, Esperanza;Snutch, Terrance P.
通讯作者：
Snutch, Terrance P.