The cell adhesion molecule CD44 acts as a modulator of 5-HT7 receptor functions.

IF 8.2 2区生物学 Q1 CELL BIOLOGY Cell Communication and Signaling Pub Date : 2024-11-23 DOI:10.1186/s12964-024-01931-0

Saskia Borsdorf, Andre Zeug, Yuxin Wu, Elena Mitroshina, Maria Vedunova, Supriya A Gaitonde, Michel Bouvier, Michael C Wehr, Josephine Labus, Evgeni Ponimaskin

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引用次数: 0

Abstract

Background: Homo- and heteromerization of G protein-coupled receptors (GPCRs) plays an important role in the regulation of receptor functions. Recently, we demonstrated an interaction between the serotonin receptor 7 (5-HT7R), a class A GPCR, and the cell adhesion molecule CD44. However, the functional consequences of this interaction on 5-HT7R-mediated signaling remained enigmatic.

Methods: Using a quantitative FRET (Förster resonance energy transfer) approach, we determined the affinities for the formation of homo- and heteromeric complexes of 5-HT7R and CD44. The impact of heteromerization on 5-HT7R-mediated cAMP signaling was assessed using a cAMP responsive luciferase assay and a FRET-based cAMP biosensor under basal conditions as well as upon pharmacological modulation of the 5-HT7R and/or CD44 with specific ligands. We also investigated receptor-mediated G protein activation using BRET (bioluminescence resonance energy transfer)-based biosensors in both, homo- and heteromeric conditions. Finally, we analyzed expression profiles for 5-HT7R and CD44 in the brain during development.

Results: We found that homo- and heteromerization of the 5-HT7R and CD44 occur at similar extent. Functionally, heteromerization increased 5-HT7R-mediated cAMP production under basal conditions. In contrast, agonist-mediated cAMP production was decreased in the presence of CD44. Mechanistically, this might be explained by increased Gαs and decreased GαoB activation by 5-HT7R/CD44 heteromers. Unexpectedly, treatment of the heteromeric complex with the CD44 ligand hyaluronic acid boosted constitutive 5-HT7R-mediated cAMP signaling and receptor-mediated transcription, suggesting the existence of a transactivation mechanism.

Conclusions: Interaction with the hyaluronan receptor CD44 modulates both the constitutive activity of 5-HT7R as well as its agonist-mediated signaling. Heteromerization also results in the transactivation of 5-HT7R-mediated signaling via CD44 ligand.

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细胞粘附分子 CD44 是 5-HT7 受体功能的调节剂。

背景：G 蛋白偶联受体（GPCR）的同源和异源化在调节受体功能方面发挥着重要作用。最近，我们证实了 A 类 GPCR 血清素受体 7（5-HT7R）与细胞粘附分子 CD44 之间的相互作用。然而，这种相互作用对 5-HT7R 介导的信号转导的功能影响仍然是个谜：方法：我们使用定量 FRET（佛斯特共振能量转移）方法测定了 5-HT7R 和 CD44 形成同源和异源复合物的亲和力。我们使用一种 cAMP 反应荧光素酶测定法和一种基于 FRET 的 cAMP 生物传感器评估了异构化对 5-HT7R 介导的 cAMP 信号转导的影响。我们还使用基于 BRET（生物荧光共振能量转移）的生物传感器研究了同源和异源条件下受体介导的 G 蛋白活化。最后，我们分析了大脑发育过程中 5-HT7R 和 CD44 的表达谱：结果：我们发现 5-HT7R 和 CD44 的同源和异源化程度相似。在功能上，异构化增加了基础条件下 5-HT7R 介导的 cAMP 生成。相反，在 CD44 存在的情况下，激动剂介导的 cAMP 生成减少。从机理上讲，这可能是由于 5-HT7R/CD44 异构体增加了 Gαs 的活化，减少了 GαoB 的活化。意想不到的是，用 CD44 配体透明质酸处理异构体复合物会增强组成型 5-HT7R 介导的 cAMP 信号转导和受体介导的转录，这表明存在一种转录激活机制：结论：与透明质酸受体 CD44 的相互作用可调节 5-HT7R 的组成活性及其激动剂介导的信号转导。异构化也会通过 CD44 配体导致 5-HT7R 介导的信号转导。

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来源期刊

Cell Communication and Signaling CELL BIOLOGY-

CiteScore

11.00

自引率

0.00%

发文量

180

期刊介绍： Cell Communication and Signaling (CCS) is a peer-reviewed, open-access scientific journal that focuses on cellular signaling pathways in both normal and pathological conditions. It publishes original research, reviews, and commentaries, welcoming studies that utilize molecular, morphological, biochemical, structural, and cell biology approaches. CCS also encourages interdisciplinary work and innovative models, including in silico, in vitro, and in vivo approaches, to facilitate investigations of cell signaling pathways, networks, and behavior. Starting from January 2019, CCS is proud to announce its affiliation with the International Cell Death Society. The journal now encourages submissions covering all aspects of cell death, including apoptotic and non-apoptotic mechanisms, cell death in model systems, autophagy, clearance of dying cells, and the immunological and pathological consequences of dying cells in the tissue microenvironment.