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

粘附G蛋白偶联受体（aGPCR）是第二大类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，它们的功能，特别是它们的信号传导机制知之甚少。aGPCR的最古老的亚家族之一是latrophilin，其存在于无脊椎动物以及脊椎动物中，因此可以被认为是这类的原型受体。Latrophilins参与神经生理和发育过程。已经表明，LAT-1是模式生物C. elegans介导两个信号。一个信号通过七个跨膜结构域（7 TM）和C端转导，另一个信号仅需要胞外N端。这两个可分离的功能的分子机制是未知的。然而，这种假定的顺式和反式信号的aGPCR的成员之间的GPCR superfamily.The拟议的研究项目集中在两个目标：1）分析的原型aGPCR latrophilin的信号转导机制在分子水平上和2）连接这些特定的生物学背景。基于自己的初步研究，这些目标将实现使用在体内测定分析latrophilin活性在C。优雅为了更好地了解LAT-1在C. elegans其在生育中的作用将被表征。随后，这两种假设的信号模式将在生物学背景下进行研究。不同LAT-1结构域的需求，LAT-1的时间个体发育方面和细胞内信号传导也将是该项目的重点。这些参数将在所有生物学背景下研究，如胚胎发育。 该研究项目的提出将大大有助于了解latrophilin在C.优雅此外，研究结果将对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学潜力。

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.