The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).
The light peak of the electroretinogram is dependent on voltage-gated calcium channels and antagonized by bestrophin (best-1).
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DOI：
10.1085/jgp.200509473
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发表时间：
2006-05
影响因子：
3.8
通讯作者：
Marmorstein, Alan D
中科院分区：
文献类型：
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作者：
Marmorstein, Lihua Y;Wu, Jiang;McLaughlin, Precious;Yocom, John;Karl, Mike O;Neussert, Rudgar;Wimmers, Soenke;Stanton, J Brett;Gregg, Ronald G;Strauss, Olaf;Peachey, Neal S;Marmorstein, Alan D
编码Bestrophin(BEST-1)的VMD2基因突变导致最佳卵黄样黄斑营养不良(BMD)、成人型卵黄样黄斑营养不良(AVMD)和常染色体显性遗传性玻璃体视网膜脉络膜病(ADVIRC)。BMD与AVMD的区别在于闪光视网膜电信号没有变化时，眼电光峰(LP)减弱。尽管Lp被认为是由BEST-1产生的，但我们发现VMD2−/−小鼠的Lp亮度反应增强，幅度正常，与Vmd2+/+小鼠相比，细胞CL−电流没有差异。推测BEST-1对钙离子的敏感性，以及我们最近观察到的BEST-1改变电压依赖性钙通道(VDCC)动力学的研究，使我们研究了VDCC在LP中的作用。尼莫地平降低了LP，导致我们研究了VDCCβ亚单位突变小鼠。在VDCC的β4亚单位中存在功能突变的嗜睡小鼠，在LP亮度反应中表现出显著的变化，确立了钙在LP生成中的作用。VMD2−/−小鼠视网膜色素上皮细胞在三磷酸腺苷刺激下[Ca++]i升高，其反应性是VMD2+/+鼠视网膜色素上皮细胞的5倍，这表明BEST-1可以抑制与LP相关的[Ca++]i升高。我们的结论是，受β4亚单位调控的VDCC是产生LP所必需的，BEST-1可能通过调节VDCC功能来拮抗LP的亮度反应。此外，我们认为与BMD相关的视力丧失不是由与LP减少相同的病理过程引起的，而是由BEST-1对其他细胞过程的未知作用引起的。
Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2 −/− mice and no differences in cellular Cl− currents in comparison to Vmd2 +/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC β-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the β4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2 −/− mice exhibited a fivefold greater response than Vmd2 +/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a β4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.