Project 02

Physiological relevance and signaling mechanisms of the Adhesion GPCR GPR110 

Simone Prömel, Leipzig University

Team members
Sandra Huth

Project Description
Adhesion G protein-coupled receptors (aGPCRs) fulfil essential functions in developmental, immunological and neurological processes and have been shown to be highly relevant in various pathological settings. Their exceptional architecture indicates unique signaling mechanisms for this receptor class. One group of aGPCRs which is highly suitable for studies on activation and signaling due to the conservation and common ancestry of its members is the cluster of Gpr110/Adgrf1, Gpr111/Adgrf2, Gpr115/Adgrf4 and Gpr116/Adgrf5. It has been shown that among receptors of this cluster, each aGPCR mediates distinct signals, but a tethered agonist derived from one receptor is able to activate several members of this group. Several studies suggest that these receptors are associated with vital biological processes with GPR110 as one of the oldest members being predominantly linked to metabolic functions. Despite these indications and their interesting signaling capacities, their physiological functions remain vastly elusive precluding the evaluation of the impact of their signals. A mouse model knockout for Gpr110 revealed that this receptor potentially plays a role in regulation of metabolic processes and renal function.

The proposed project focuses on elucidation of the physiological functions of GPR110 and the implications of its signaling mechanisms and targets two aims:
1. Analysis of the role of GPR110 in renal function and regulation of metabolic processes and 2. delineation of the signaling mechanisms underlying these physiological functions. Based on own preliminary data, these aims will be achieved using a combination of in vivo, ex vivo and in vitro analyses centering around the existing knockout mouse model, tissue culture models and the acquired knowledge about signaling of the receptor. The physiological relevance of GPR110 in the kidney and a potential role in renal injury will be elucidated as well as its impact on regulation of metabolic processes. Subsequently, receptor signalling on a molecular level in the identified contexts will be analyzed. Receptor activation and interaction partners will also be a focus of the project.
The proposed research project will substantially contribute to the understanding of the physiological relevance of the aGPCR GPR110. Moreover, findings will give further profound insights into the signal transduction of aGPCRs, potentially aiding the evaluation of the pharmacological potential of this receptor class.

 

Publications

Groß VE, Gershkovich MM, Schöneberg T, Kaiser A, Prömel S. NanoBRET in C. elegans illuminates functional receptor interactions in real time. BMC Mol Cell Biol. 2022 Jan 31;23(1):8. doi: 10.1186/s12860-022-00405-w. PMID: 35100990. 

Heshof R, Visscher B, Prömel S, Hughes S (2019) Large-scale cultivation of Caenorhabditis elegans in a bioreactor using a labor-friendly fed-batch approach. 
Biotechniques. doi: 10.2144/btn-2019-0008. [Epub ahead of print]. 

Morgan RK, Anderson GR, Araç D, Aust G, Balenga N, Boucard A, Bridges JP, Engel FB, Formstone CJ, Glitsch MD, Gray RS, Hall RA, Hsiao CC, Kim HY, Knierim AB, Kusuluri DK, Leon K, Liebscher I, Piao X, Prömel S, Scholz N, Srivastava S,Thor D, Tolias KF, Ushkaryov YA, Vallon M, Van Meir EG, Vanhollebeke B, Wolfrum U, Wright KM, Monk KR, Mogha A (2019). The expanding functional roles and signaling mechanisms of adhesion G protein-coupled receptors. Annals of the New York Academy of Sciences. doi: 10.1111/nyas.14094. [Epub ahead of print] 

Röthe J, Thor D, Winkler J, Knierim A, Binder C, Huth S, Kraft R, Rothemund S, Schöneberg T, Prömel S (2019) Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release. Cell Reports. 26: 1573–1584. 

Schöneberg T, Prömel S (2019) Latrophilins and Teneurins in Invertebrates: No Love for Each Other? Front. Neurosci. 

Matúš D, Prömel S (2018) G Proteins and GPCRs in C. elegans Development: A Story of Mutual Infidelity. Journal of Developmental Biology. 2018; 6. pii: E28. doi: 10.3390/jdb6040028.