The Role of the Voltage-Gated Potassium Channel Proteins Kv8.2 and Kv2.1 in Vision and Retinal Disease: Insights from the Study of Mouse Gene Knock-Out Mutations
The Role of the Voltage-Gated Potassium Channel Proteins Kv8.2 and Kv2.1 in Vision and Retinal Disease: Insights from the Study of Mouse Gene Knock-Out Mutations
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DOI：
10.1523/eneuro.0032-19.2019
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发表时间：
2019-01-01
期刊：
影响因子：
3.4
通讯作者：
Carvalho, Livia S.
中科院分区：
文献类型：
--
作者：
Hart, Nathan S.;Mountford, Jessica K.;Carvalho, Livia S.
编码电压门控K+通道蛋白Kv8.2的KCNV2基因突变会导致一种独特的视锥细胞营养不良症，并伴有超常的视杆反应(CDSRR)。Kv8.2通道亚基只有与KCNB1基因编码的Kv2.1亚基在异源四聚体中结合才能形成功能通道。CDSRR病的表型表明，光感受器的适应受到破坏。受影响的个体的视网膜电信号(ERG)反应显示视杆和视锥活动受到抑制，但这种疾病的不同之处是对明亮闪光的视杆反应异常。在这里，我们利用小鼠两个基因的敲除突变来研究CDSRR的病理生理学。Kv8.2基因敲除(KO)小鼠表现出与人类疾病的许多相似之处，包括a波抑制和b波反应升高，并受到强光刺激。光学相干断层扫描(OCT)成像和免疫组织化学显示6个月龄Kv8.2 KO视网膜的变化主要局限于外核层(ONL)，而外节看起来完好无损。此外，整个视网膜的TUNEL阳性细胞显著增加。Kv2.1 KO和双KO小鼠也表现出严重的a波抑制，但没有升高的b波反应。有趣的是，在所有三种KO基因型中，c-波都完全不存在。这些具有同质通道或完全缺乏通道的KO线的差异性反应为进一步了解K+通道在ERG a波、b波和c波成分的产生中的作用提供了进一步的见解。
Mutations in the KCNV2 gene, which encodes the voltage-gated K+ channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K+ channels in the generation of the a-, b-, and c-wave components of the ERG.