Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109-0660, USA.
Front Biosci (Landmark Ed). 2022 May 10;27(5):150. doi: 10.31083/j.fbl2705150.
The structures and activities of invertebrate sulfakinins that influence gut motility and heart rate are like the vertebrate cholecystokinin (CCK) peptides. Typical of sulfakinin precursors encodes non-sulfated drosulfakinin I (nsDSK I; FDDYGHMRF-NH2) and nsDSK II (GGDDQFDDYGHMRF-NH2) that bind DSK-R1 and DSK-R2. To explore the role of the nsDSK II N-terminal extension (GGDDQ) in gut we delineated its structure-activity relationship (SAR) and identified novel agonists. We then predicted the nsDSK II extension SAR is tissue specific consistent with cardiac CCK structure activity and signaling being different from gut.
To evaluate our hypothesis, we tested single-substituted alanine and asparagine analogs in heart.
We found alanyl-substituted analogs were less active in heart than nsDSK II; in gut they include a super agonist and a protean agonist. Additionally, we discovered ns[N4]DSK II was more active than nsDSK II in pupal heart, while ns[N3]DSK II was inactive. In contrast, ns[N3]DSK II and ns[N4]DSK II were super agonists in adult heart, yet inactive in larva. Although we reported nsDSK II acts through DSK-R2 in gut, its identity in heart was unknown.
Here we reviewed ligand-receptor interactions in conjunction with SAR data to suggest nsDSK II acts through DSK-R1 in heart consistent with sulfakinin tissue-specific signaling.
影响肠道蠕动和心率的无脊椎动物磺酰基肽的结构和活性与脊椎动物胆囊收缩素（CCK）肽相似。磺酰基肽前体的典型特征是编码非磺化的 drosulfakinin I（nsDSK I；FDDYGHMRF-NH2）和 nsDSK II（GGDDQFDDYGHMRF-NH2），它们与 DSK-R1 和 DSK-R2 结合。为了探索 nsDSK II N 端延伸（GGDDQ）在肠道中的作用，我们描绘了它的结构-活性关系（SAR）并鉴定了新的激动剂。然后，我们预测 nsDSK II 延伸 SAR 是组织特异性的，与心脏 CCK 结构活性和信号传递不同，与肠道不同。
为了验证我们的假设，我们在心脏中测试了单取代的丙氨酸和天冬酰胺类似物。
我们发现丙氨酸取代的类似物在心脏中的活性比 nsDSK II 低；在肠道中，它们包括一个超级激动剂和一个多变的激动剂。此外，我们发现 ns[N4]DSK II 在蛹心脏中的活性比 nsDSK II 高，而 ns[N3]DSK II 则没有活性。相反，ns[N3]DSK II 和 ns[N4]DSK II 在成年心脏中是超级激动剂，但在幼虫中没有活性。尽管我们报道 nsDSK II 在肠道中通过 DSK-R2 发挥作用，但它在心脏中的身份尚不清楚。
在这里，我们结合 SAR 数据回顾了配体-受体相互作用，提出 nsDSK II 通过 DSK-R1 在心脏中发挥作用，这与磺酰基肽的组织特异性信号传递一致。
