Spatiotemporal transregulation of D1-like angiotensin receptors in genetically...

G蛋白偶联激酶4(GRK4)基因变体(R65L、A142V和A486V)选择性脱敏 多巴胺-1受体(DIR)，而不是D5R，它上调血管紧张素1型受体(ATIR)。 脱敏的DIR(利钠药)和上调的ATIR(抗心房利药)的最终结果是净钠 被肾脏重吸收。然而，导致DIR脱敏的分子机制，ATIR 上调，以及这两个途径对净钠代谢的整合还不是很清楚。 我们假设DIR、D5R和ATIR的膜定位和最终活性是 受齐聚和空间定向调控，通过支架蛋白(例如小窝蛋白-L(CAV1))，其 最终调节它们与细胞内第二信使的相互作用。具体地说，GRK4结合到 小窝-L(CAV1)，它被基因变异的存在所打断。我们进一步假设一个 分子三聚体D1R/CAV1/GRK4的结合可能是多巴胺能抑制中枢神经系统发育所必需的 NaKATPase活性通过细胞内内化与适配蛋白-2(AP-2)结合。特定目标 1将研究DIR、D5R、ATIR和CAV1的时空反调及其与 细胞内的第二信使。为了增加我们的研究与人类生理学和 病理生理学，我们将在60个人肾近端小管细胞系(RPTCs)中研究这些现象 已经对GRK4变异体进行了基因分型。特定目标2将研究细胞的时空反调。 DIR、D5R、ATIR和CAVI及其对人体主要钠转运体活性的影响 RPTCs NaKATPase和NHE3。GKR4基因变异对单个RPTC影响的研究 代表广泛遗传多样性的生理学将提高我们对肾脏近端如何 肾小管控制肾脏钠的排泄，并为开发新的治疗靶点。 有针对性和个性化的抗高血压治疗药物。

G protein-coupled kinase type 4 (GRK4) gene variants (R65L, A142V, and A486V) selectively desensitizes the dopamine-1 receptor (DIR) and not the D5R, which upregulates the angiotensin type 1 receptor (ATIR). The net result of a desensitized DIR (natriuretic) and upregulated ATIR (antinatriuretic) is a net sodium reabsorption by the kidney. However, the molecular mechanisms responsible for DIR desensitization, ATIR upregulation, and the integration of these two pathways on net sodium metabolism are not well understood. We hypothesize that the membrane localization and ultimate activity of the DIR, D5R, and ATIR are regulated by oligomerization and spatial orientation via scaffolding proteins (e.g. caveolin-l (CAV1)), which ultimately regulate their interaction with intracellular second messengers. Specifically, GRK4 binds to caveolin-l (CAV1) which is interrupted by the presence of gene variants. We further hypothesize that a molecular trimeric D1R/CAV1/GRK4 association may be necessary for dopaminergic inhibition of NaKATPase activity via intracellular internalization in conjunction with adapter protein-2 (AP-2). Specific Aim 1 will examine the spatiotemporal transregulation of the DIR, D5R, ATIR, and CAV1 and their link to intracellular second messengers. In order to increase the relevance of our studies to human physiology and pathophysiology, we will study these phenomenon in 60 human renal proximal tubular cells (RPTCs) lines that have been genotyped for GRK4 variants. Specific Aim 2 will study spatiotemporal transregulation of the DIR, D5R, ATIR, and CAVIand their effect on the activity of the principal sodium transporters in human RPTCs NaKATPase and NHE3. The study of the effect of gene variants of GKR4 on the single RPTC physiology representing wide genetic diversity will improve our understanding of how the renal proximal tubule controls renal sodium excretion, and lead to potential novel therapeutic targets for the development of targeted and personalized antihypertensive therapeutics.