Project 01

Functional analysis of the adhesion GPCR class in Drosophila

Tobias Langenhan & Nicole Scholz, Leipzig University

Team members
Fernando Vieira Contreras
Anne Bormann
Marek Körner

Project Description
Adhesion-GPCRs (aGPCRs) possess a highly modular blueprint that enables canonical G-protein and beta-arrestin signaling through a heptahelical transmembrane unit (7TM) as well as adhesion and target recognition mediated by large extracellular domains. In contrast to other GPCR families, aGPCRs engage primarily with insoluble ligands presented by adjacent cells or the extracellular matrix. The ligand nature and the conspicuous receptor geometry may reflect the capacity of aGPCRs to sense mechanical cues, an unusual sensory modality within the GPCR realm. Several studies have demonstrated aGPCR function in mechanobiological phenomena, however several principal mechanistic aspects of how these receptors operate, which signaling cascades they trigger in response to mechanical stimulation and finally how these signals are implemented into the cellular program to modulate its physiology are unknown. Furthermore, recent work on Latrophilin/dCirl indicates that the dimension of the ECD shapes its mechanoceptive profile and that alternative splicing of Latrophilin/dCirl mRNA yields receptor isoforms that vary greatly in ECD size. This project utilizes Drosophila as an in vivo test tube to investigate the biological relevance of natively occuring dCIRL receptor isoforms with a particular focus on their mechanosensing and signaling capabilities. We will also explore the possibility that aGPCRs employ alternative signaling routes to shape cellular behavior. The second part of this project focuses on the functional characterization of two newly identified, unsought aGPCRs (CG11318 and CG15556). Finally, we will explore if they operate in mechanobiological contexts in vivo and if so how these inputs are integrated to modify the biology of the expressing tissues. 


Paul MM, Dannhäuser S, Morris L, Mrestani A, Hübsch M, Gehring J, Hatzopoulos GN, Pauli M, Auger GM, Bornschein G, Scholz N, Ljaschenko D, Müller M, Sauer M, Schmidt H, Kittel RJ, DiAntonio A, Vakonakis I, Heckmann M, Langenhan T (2022) The human cognition-enhancing CORD7 mutation increases active zone number and synaptic release. Brain. 2022 Jan 12:awac011. Epub ahead of print. PMID: 35022694. 

Heydasch U, Kessler R, Warnke JP, Eschrich K, Scholz N, Bigl M. Functional diversity of PFKFB3 splice variants in glioblastomas. PLoS One. 2021; 16:e0241092. 

Smolič T, Tavčar P, Horvat A, Černe U, Vasle AH, Tratnjek L, Kreft ME, Scholz N, Matis M, Petan T, Zorec R, Vardjan N (2021) Astrocytes in stress accumulate lipid droplets. Glia. Online ahead of print. 

Beliu G, Altrichter S, Guixà-González R, Hemberger M, Brauer I, Dahse AK, Scholz N, Wieduwild R, Kuhlemann A, Batebi H, Seufert F, Pérez-Hernández G, Hildebrand PW, Sauer M, Langenhan L (2021) Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain. Molecular Cell. 81: 1–17. 

Mathiasen S, Palmisano T, Perry NA, Stoveken HM, Vizurraga A, McEwen DP, Okashah N, Langenhan T, Inoue A, Lambert NA, Tall GG, Javitch JA (2020) G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. Nat Chem Biol. 16: 1343-1350.  

Blanco-Redondo B, Nuwal N, Kneitz S, Nuwal T, Halder P, Liu Y, Ehmann N, Scholz N, Mayer A, Kleber J, Kähne T, Schmitt D, Sadanandappa MK, Funk N, Albertova V, Helfrich-Förster C, Ramaswami M, Hasan G, Kittel RJ, Langenhan T, Gerber B, Buchner E (2019) Implications of the Sap47 null mutation for synapsin phosphorylation, longevity, climbing, and behavioural plasticity in adult Drosophila. Journal of Experimental Biology. pii: jeb.203505. doi: 10.1242/jeb.203505. [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 SScholz 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] 

Langenhan T (2019) Adhesion G protein-coupled receptors – candidate metabotropic mechanosensors and novel drug targets. Basic & Clinical Pharmacology & Toxicology. doi: 10.1111/bcpt.13223. [Epub ahead of print]. 

Scholz NLangenhan TSchöneberg T (2019) Revisiting the classification of adhesion GPCRs. Annals of the New York Academy of Sciences. doi: 10.1111/nyas.14192. [Epub ahead of print] 

Scholz N, Ehmann N, Sachidanandan D, Imig C, Cooper BH, Jahn O, Reim K, Brose N, Meyer J, Lamberty M, Altrichter S, Bormann A, Hallermann S, Pauli M, Heckmann M, Stigloher C, Langenhan TKittel RJ (2019) Complexin cooperates with Bruchpilot to tether synaptic vesicles to the active zone cytomatrix. J Cell Biol. 218: 1011-1026. 

Blanco-Redondo B, Langenhan T (2018) Parallel Genomic Engineering of Two Drosophila Genes Using Orthogonal attB/attP Sites. G3 (Bethesda). 8: 3109-3118. 

Scholz N (2018) Cancer Cell Mechanics: Adhesion G Protein-coupled Receptors in Action? Front Oncol. 8: 59.