Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117558, Singapore.
NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore, 119077, Singapore.
Sci Rep. 2023 Nov 22;13(1):20439. doi: 10.1038/s41598-023-47710-8.
Atrial natriuretic peptide (ANP) is a peptide hormone that regulates blood pressure and volume. ANP interacts with natriuretic peptide receptor-A (NPR-A) to lower the blood pressure through vasodilation, diuresis and natriuresis. Previously, we designed two human ANP analogues, one with exclusively diuretic function (DGD-ANP) and the other with exclusively vasodilatory function (DRD-ANP). Although both ANP analogues interact with NPR-A, their ability to produce cGMP was different. Three alternatively spliced isoforms of NPR-A were previously identified in rodents. Here, we evaluated the putative human isoforms for their cGMP production independently and in combination with WT NPR-A in various percentages. All three NPR-A isoforms failed to produce cGMP in the presence of ANP, DGD-ANP, or DRD-ANP. Co-expression of isoforms with WT NPR-A were found to significantly impair cGMP production. Considering the differential tissue expression levels of all three spliced isoforms in rodents have previously been demonstrated, the existence of these non-functional receptor isoforms may act as negative regulator for ANP/NPR-A activation and fine-tune cGMP production by WT NPR-A to different degree in different tissues. Thus, NPR-A isoforms potentially contribute to tissue-specific functions of ANP.
心房利钠肽（ANP）是一种调节血压和容量的肽类激素。ANP 通过血管舒张、利尿和利钠作用与利钠肽受体-A（NPR-A）相互作用降低血压。先前，我们设计了两种人类 ANP 类似物，一种具有利尿功能（DGD-ANP），另一种具有血管舒张功能（DRD-ANP）。尽管两种 ANP 类似物都与 NPR-A 相互作用，但它们产生 cGMP 的能力不同。先前在啮齿动物中鉴定了 NPR-A 的三种选择性剪接的同工型。在这里，我们独立评估了推定的人类同工型与 WT NPR-A 以不同百分比组合的 cGMP 产生情况。在存在 ANP、DGD-ANP 或 DRD-ANP 的情况下，所有三种 NPR-A 同工型均未能产生 cGMP。发现同工型与 WT NPR-A 的共表达显着损害 cGMP 的产生。考虑到先前已经证明所有三种剪接同工型在啮齿动物中的组织表达水平存在差异，这些无功能受体同工型的存在可能作为 ANP/NPR-A 激活的负调节剂，以不同程度在不同组织中精细调节 WT NPR-A 的 cGMP 产生。因此，NPR-A 同工型可能有助于 ANP 的组织特异性功能。
