Department of Physiology, University of Arizona, Tucson, AZ, USA; Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
Exp Eye Res. 2024 Oct;247:110049. doi: 10.1016/j.exer.2024.110049. Epub 2024 Aug 14.
The retina has low dopamine levels early in diabetes. To determine how low dopamine levels affected dopamine signaling, the effects of dopamine receptor agonists and mRNA localization were measured after 6 weeks of diabetes. Whole retina ex vivo electroretinogram (ERG) recordings were used to analyze how dopamine type 1 receptor (D1R) and type 4 (D4R) agonists change the light-evoked retinal responses of non-diabetic and 6-week diabetic (STZ injected) mouse retinas. Fluorescence in situ hybridization was utilized to analyze D4R and D1R mRNA locations and expression levels. D4R activation reduced A- and B-wave ERG amplitudes and increased B-wave implicit time and rise-time in the non-diabetic group without a corresponding change in the diabetic group. D1R activation increased B-wave rise-time and oscillatory potential peak time in the non-diabetic group also with no change in the diabetic group. The lack of responsivity to D1R or D4R agonists shows an impairment of dopamine signaling in the diabetic retina. D4R mRNA was found primarily in the outer nuclear layer where photoreceptor cell bodies reside. D1R mRNA was found in the inner nuclear layer and ganglion cell layer that contain bipolar, amacrine, horizontal and ganglion cells. There was no change in D4R or D1R mRNA expression between the non-diabetic and diabetic retinas. This suggests that the significant dopamine signaling changes observed were not from lower receptor expression levels but could be due to changes in dopamine receptor activity or protein levels. These studies show that changes in retinal dopamine signaling could be an important mechanism of diabetic retinal dysfunction.
糖尿病早期视网膜中的多巴胺水平较低。为了确定多巴胺水平降低如何影响多巴胺信号转导，在糖尿病 6 周后测量了多巴胺受体激动剂和 mRNA 定位的影响。全视网膜离体视网膜电图（ERG）记录用于分析多巴胺 1 型受体（D1R）和 4 型（D4R）激动剂如何改变非糖尿病和 6 周糖尿病（STZ 注射）小鼠视网膜的光诱发视网膜反应。荧光原位杂交用于分析 D4R 和 D1R mRNA 位置和表达水平。D4R 激活降低了非糖尿病组的 A 和 B 波 ERG 幅度，并增加了 B 波的隐含时间和上升时间，而糖尿病组则没有相应的变化。D1R 激活增加了非糖尿病组的 B 波上升时间和振荡电位峰值时间，而糖尿病组则没有变化。缺乏对 D1R 或 D4R 激动剂的反应表明糖尿病视网膜中的多巴胺信号转导受损。D4R mRNA 主要存在于外核层，其中包含感光细胞体。D1R mRNA 存在于内核层和神经节细胞层中，其中包含双极、无长突细胞、水平和神经节细胞。非糖尿病和糖尿病视网膜之间 D4R 或 D1R mRNA 表达没有变化。这表明观察到的多巴胺信号显著变化不是由于受体表达水平降低引起的，而是可能由于多巴胺受体活性或蛋白水平的变化引起的。这些研究表明，视网膜多巴胺信号转导的变化可能是糖尿病性视网膜功能障碍的重要机制。
