Project 1

Functional analysis of genetically encoded aGPCR signaling states

Tobias Langenhan, Leipzig University

Team members
Nicole Scholz

Project Description
Adhesion-GPCRs (aGPCRs) possess a highly modular architecture displaying protein regions that permit adhesion and target recognition through protein interactions, and G protein signaling through a heptahelical transmembrane unit (7TM). Evidence from several aGPCRs suggests that these receptors differentially engage with at least two independent activity contexts. In principle, this renders aGPCRs a receptor entity capable to handle multiple signals. These activities molecularly differ from each other in that one depends on the presence of the 7TM and intracellular domain (ICD), whereas the other one functions 7TM-independently provided that its extracellular domain (ECD) remains anchored to the cell membrane, e.g. through a single transmembrane helix. Genetic complementation experiments with full and truncated aGPCR homologs revealed a picture on aGPCR signalling, which is consistent with a hybrid receptor model, in which the ECD of an aGPCR is required for biological activities that differ from the activities exerted by the 7TM/ICD (i.e. adhesion vs transmembrane signaling, trans vs cis-protein interactions). However, if and how these bimodal activities are differentially regulated under physiological conditions is unclear thus far. Further, it is unknown whether an aGPCR molecule can receive its different signal inputs simultaneously, or if stimulus encounter restricts the receptor to one signaling state. This project centres on the hypothesis that splicing constitutes a mechanism to control the production of different dCirl mRNA species. Preliminary data show that at least two different types of dCirl transcripts are expressed in the fly resulting in two disparate receptor isoforms: a full-length receptor (dCIRL7TM), and a shortened receptor protein, which contains the ECD, a single transmembrane helix and an alternative ICD (dCIRL1TM). During the project the hypothesis will be tested that these dCIRL isoforms correspond to naturally occuring 7TM-dependent or 7TM-independent receptor states. The endogenous function of each isoform will be studied within an in vivo environment using Drosophila.

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)

Langenhan T#, Piao X#, Monk KR# (2016) Adhesion G protein-coupled receptors in nervous system development and disease. Nature Reviews Neuroscience 17:550-61.

Backhaus P, Langenhan T, Neuser K (2016) Effects of transgenic expression of botulinum toxins in Drosophila. Journal of Neurogenetics 30:22-31.

Nieberler M, Kittel RJ, Petrenko AG, Lin HH#, Langenhan T# (2016) Control of Adhesion GPCR Function Through Proteolytic Processing. Handbook of Experimental Pharmacology 234:83-109. 

Scholz N#, Monk KR, Kittel RJ, Langenhan T# (2016) Adhesion GPCRs as a Putative Class of Metabotropic Mechanosensors. Handbook of Experimental Pharmacology 234:221-247. 

Monk K, Hamann J, Langenhan T, Nijmeijer S, Schöneberg T, Liebscher I (2015) Adhesion GPCRs: From In Vitro Pharmacology to In Vivo Mechanisms. Molecular Pharmacology 88:617-623. Download_Icon 

Langenhan T#, Barr MM, Bruchas MR, Ewer J, Griffith LC, Maiellaro I, Taghert PH, White BH, Monk KR# (2015) Model Organisms in GPCR Research. Molecular Pharmacology 88:596-603.Download_Icon 

Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R, Lakshmanan V, Kittel RJ#, Langenhan T# (2015) The Adhesion GPCR Latrophilin/CIRL Shapes Mechanosensation. Cell Reports 11:866-874.

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*, Schiöth HB*,# (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.