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.

心房钠尿肽（ANP）是一种调节血压和容量的肽激素。 ANP 与利尿钠肽受体-A (NPR-A) 相互作用，通过血管舒张、利尿和尿钠排泄来降低血压。此前，我们设计了两种人类ANP类似物，一种仅具有利尿功能（DGD-ANP），另一种仅具有血管舒张功能（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。先前在啮齿类动物中鉴定出 NPR-A 的三种选择性剪接亚型。在这里，我们独立评估了假定的人类亚型的 cGMP 生产，并与不同百分比的 WT NPR-A 结合。在 ANP、DGD-ANP 或 DRD-ANP 存在的情况下，所有三种 NPR-A 亚型均无法产生 cGMP。研究发现同种型与 WT NPR-A 的共表达会显着损害 cGMP 的产生。考虑到啮齿动物中所有三种剪接亚型的差异组织表达水平先前已被证明，这些非功能性受体亚型的存在可能充当 ANP/NPR-A 激活的负调节因子，并微调 WT NPR-A 的 cGMP 产生不同组织中程度不同。因此，NPR-A 亚型可能有助于 ANP 的组织特异性功能。