D5 receptor antioxidant activity and hypertension

在人类高血压和遗传性高血压的啮齿动物模型中，存在多巴胺产生和受体功能的异常；一些多巴胺受体基因及其调节基因位于与高血压相关的基因座上。在小鼠体内，D5受体的破坏会导致高血压。D5受体是两个类似D1型受体之一(D1和D5)。当小鼠的D5受体被破坏时，多受体级联通过中枢和外周机制导致高血压。这种普遍的异常可能与活性氧(ROS)的生成增加有关。总体假设是，与其他多巴胺受体不同的是，D5受体在结构性上不同于其他多巴胺受体，它的作用是防止ROS的增加，而不同于其他多巴胺受体，它的作用是防止由于D5受体功能受损或高血压而导致的ROS形成的增加。D5受体功能受损的后果可能是ROS增加。特异靶1将在D5基因敲除小鼠和表达D5受体突变的细胞中建立ROS增加的机制。我们将确定D5基因敲除小鼠和表达D5受体突变体的细胞中特异性增加的ROS。我们将确定：(A)磷脂酶D(PLD)在ROS中的具体作用，因为PLD产生的磷脂酸是NADPH活性的有效激活剂；(B)蛋白激酶A(PKA)活性降低，从而无法终止NADPH氧化酶的活性，从而促进正在进行的ROS的产生。初步数据显示，多态的D5受体未能增加cAMP的产生，也增加了ROS。因此，D5受体不能产生cAMP/PKA，从而抑制NADPH氧化酶活性，可以增加ROS。特异目的2将建立D5基因敲除小鼠抗氧化活性和细胞氧化酶歧化酶缺乏的机制。特异靶3将验证多巴胺通过D1/D5受体起到对抗血管紧张素II的升压作用的假说。这些研究将确定AT1和D1/D5受体在高血压发病机制中的相互作用。人类存在D5受体单核苷酸多态，刺激cAMP产生的能力降低，因此对D5受体的研究可能有助于揭示人类高血压的发病机制。

Abnormalities in dopamine production and receptor function are present in human essential hypertension and rodent models of genetic hypertension; some dopamine receptor genes and their regulators are in loci linked to hypertension. Disruption of the D5 receptor, one of the two D1-like receptors (D1 and D5), in mice produces hypertension. A multi- receptor cascade causes high blood pressure, via central and peripheral mechanisms, when the D5 receptor is disrupted in mice. This widespread abnormality may be related to the increased generation of reactive oxygen species (ROS). The overall hypothesis is that the D5 receptor, which is constitutively unlike the other dopamine receptors, acts to protect against an increase in ROS is constitutively activated unlike the other dopamine receptors, acts to protect against an increase in ROS formation engendered by impairment of D5 receptor function or by hypertension. A consequence of impaired function of the D5 receptor may be an increase in ROS. Specific aim 1 will establish the mechanism of increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific increased ROS in D5 knockout mice and cells expressing D5 receptor mutants. We will determine the specific role of: (a) phospholipase D (PLD) in ROS because phosphatidic acid, produced by PLD, is a potent activator of NADPH activity; (b) a reduced activity of protein kinase A (PKA), which thereby fails to terminate NADPH oxidase activity and hence promotes ongoing ROS production. Preliminary data indicates that a polymorphic D5 receptor that failed to increase cAMP production also increased ROS. Therefore, the failure of D5 receptors to generate cAMP/PKA, and thus, inhibition of NADPH oxidase activity, can increase ROS. Specific aim 2 will establish the mechanism of the deficient antioxidant activity in D5 knockout mice and cells oxidase dismutase. Specific aim 3 will test the hypothesis that dopamine, via D1/D5 receptors, serve to counter-act the hypertensinogenic effects of angiotensin II. These studies will determine the interactions between AT1 and D1/D5 receptors in the pathogenesis of hypertension. Single nucleotide polymorphisms of the D5 receptor with decreased ability to stimulate cAMP production are present in the human population, thus studies of D5 receptors may shed light into the pathogenesis of human essential hypertension.