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.

中文翻译：

---

与三叉神经痛相关的 CACNA1A 变异改变了 Cav2.1 通道的门控

在三叉神经痛患者中发现了编码 CaV2.1 电压门控钙通道的孔形成 α1 亚基的 CACNA1A 基因中的一种新型错义突变。该突变导致通道远端 C 端区域的脯氨酸 2455 被组氨酸 (P2455H) 取代。由于该通道在神经递质释放中的明确作用，我们的目标是在异源表达的 CaV2.1 通道中表征 P2455H 变体的生物物理特性。tsA-201 细胞中表达的野生型和突变型 CaV2.1 通道的全细胞膜片钳记录表明，该突变介导了激活和失活的电压依赖性的去极化转变。而且，P2455H 突变体大大减少了钙依赖性通道失活，这与整体功能获得一致。因此，P2455H 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 依赖性突触通信的相关变化可能有助于三叉神经痛的发展。