Project 2

Signaling mechanisms of the aGPCR Latrophilin in C. elegans

Simone Prömel, Leipzig University

Team members
Franziska Fiedler

Antje Müller

Project Description
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.

Publications

Scholz N*, Guan C*, Nieberler M*, Grotemeyer A*, Maiellaro I, Gao S, Beck S, Pawlak M, Sauer M, Asan E, Rothemund S, Winkler J, Prömel S, Nagel G, Langenhan T#, Kittel RJ# (2017) Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons. eLife (accepted for publication)

Demberg LM*, Winkler J*, Wilde C*, Simon KU, Schön J, Rothemund S, Schöneberg T, Prömel S#, Liebscher I# (2017) Activation of Adhesion G Protein-coupled Receptors: Agonist specificity of Stachel sequence-derived peptides. J Biol Chem. 292:4383-4394. 

Prömel S,  Fiedler F, Binder C, Winkler J, Schöneberg T, and Thor D (2016). Deciphering and modulating G protein signalling in C. elegans using the DREADD technology. Sci Rep. 6:28901.

Strutt D, Schnabel R, Fiedler F, Prömel S (2016) Adhesion GPCRs Govern Polarity of Epithelia and Cell Migration. Handbook of Experimental Pharmacology 234:249-274. 

Winkler J, Prömel S (2016) The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity. Worm 5(2) e1170274.

Müller A, Winkler J, Fiedler F, Sastradihardja T, Binder C, Schnabel R, Kungel J, Rothemund S, Hennig C, Schöneberg T, Prömel S (2015) PLoS Genet 11(10):e1005624.

Hamann J, Aust G, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, and Schiöth HB (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.