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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Ca_v1.4 channel activation
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A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Ca_v1.4 channel activation

机译：在X连锁性视网膜疾病中发现的CACNA1F突变改变了Ca_v1.4通道激活的电压依赖性

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摘要

Light stimuli produce graded hyperpolarizations of the photore-ceptor plasma membrane and an associated decrease in a voltage-gated calcium channel conductance that mediates release of glu-tamate neurotransmitter. The Ca_v1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the pore-forming subunit of the Ca_v1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately -30-mV shift in the voltage dependence of Ca_v1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca_v1.4 channel activity is likely to cause the unusual phenotype.
机译：光刺激产生光感受器质膜的分级超极化，并介导谷氨酸神经递质释放的电压门控钙通道电导率降低。 Ca_v1.4通道被认为与该过程有关。 CACNA1F基因编码Ca_v1.4通道的孔形成亚基，并且CACNA1F中的各种突变导致X连锁不完全先天性固定性夜盲症（CSNB2）。 CSNB2表型基础病理的分子机制仍有待建立。最近对新西兰一家人进行的临床研究发现，一种严重的视觉障碍与CSNB2有一些临床相似之处，但有明显区别。在这里，我们报告调查这种情况的病理学的分子机制。分子遗传学分析鉴定了CACNA1F中先前未描述的核苷酸取代，该核苷酸取代预计在CACNA1F残基745处编码异亮氨酸至苏氨酸取代。I745TCACNA1F等位基因在Ca_v1.4通道激活和电压依赖性的电压依赖性方面产生了明显的-30 mV的变化。大大降低了表达系统的失活动力学。这些发现暗示跨膜区段II​​S6中这种野生型残基的取代可能降低了打开通道所需的能量。总体而言，这些发现表明，涉及Ca_v1.4通道活性增加的功能获得机制可能会导致异常表型。

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