Signaling mechanisms of the Adhesion-G protein-coupled receptor latrophilin in C. elegans

粘附- g蛋白偶联受体（agpcr）是第二大的gpcr。它们参与各种重要的发育、免疫和神经过程，使它们成为有希望的药物靶点。然而，人们对它们的功能，尤其是它们的信号机制知之甚少。嗜乳蛋白是agpcr最古老的亚家族之一，它存在于无脊椎动物和脊椎动物中，因此可以被认为是这一类的原型受体。嗜乳蛋白参与神经生理和发育过程。研究表明，模式生物秀丽隐杆线虫中两个亲和蛋白同源物之一的lat1介导两个信号。一个信号通过7个跨膜结构域（7TM）和C端转导，另一个信号只需要胞外N端。这两种可分离功能的分子机制尚不清楚。然而，这种推测的agpcr的顺式和反式信号转导将是GPCR超家族成员中独特的信号转导机制。本研究项目主要集中在两个方面：1)在分子水平上分析原型aGPCR嗜乳蛋白的信号传导机制；2)将这些机制与特定的生物学环境联系起来。基于自己的初步研究，这些目标将通过在线虫体内分析嗜乳蛋白活性来实现。为了更好地理解lat1在秀丽隐杆线虫中的生理相关性，我们将对其在生殖中的作用进行表征。随后，这两种假设的信号模式将在生物学背景下进行研究。各种lat1结构域的要求，时间-个体发生方面和lat1的细胞内信号传导也将是本项目的重点。这些参数将在所有生物学背景下进行研究，如胚胎发育。本研究将对秀丽隐杆线虫嗜乳蛋白的生理意义的理解作出重要贡献。此外，这些发现将对agpcr的信号转导提供深刻的见解，可能有助于评估这类受体的药理潜力。

Adhesion-G protein-coupled receptors (aGPCRs) are the second largest class of GPCRs. They are involved in various essential developmental, immunological and neurological processes, rendering them promising drug targets. However, their functions and especially their signaling mechanisms are poorly understood. One of the oldest subfamilies of aGPCRs are latrophilins, which are present in invertebrates as well as vertebrates and thus, can be considered as prototypic receptors for this class. Latrophilins are involved in neurophysiological and developmental processes. It has been shown that LAT-1, one of two latrophilin homologs in the model organism C. elegans, mediates two signals. One signal is transduced via the seven transmembrane domain (7TM) and the C terminus, the other one only requires the extracellular N terminus. The molecular mechanisms underlying these two separable functions are unknown. However, this presumable cis- and trans-signaling of aGPCRs would be a unique signaling mechanism among members of the GPCR superfamily.The proposed research project focuses on two aims: 1) Analysis of the signaling mechanisms of the prototypic aGPCR latrophilin on a molecular level and 2) linking these to specific biological contexts. Based on own preliminary studies these aims will be achieved using an in vivo assay for the analysis of latrophilin activity in C. elegans. For a better understanding of the physiological relevance of LAT-1 in C. elegans its role in fertility will be characterized. Subsequently, both hypothesized signaling modes will be studied in the biological context identified. The requirements of various LAT-1 domains, temporal-ontogenetic aspects and intracellular signaling of LAT-1 will also be a focus of this project. These parameters will be investigated in all biological contexts latrophilin is involved in such as embryonic development. The proposed research project will substantially contribute to the understanding of the physiological relevance of latrophilin in C. elegans. Furthermore, findings will give profound insights into the signal transduction of aGPCRs, potentially aiding the evaluation of the pharmacological potential of this receptor class.