Expression of mammalian GPCRs in C. elegans generates novel behavioural responses to human ligands
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BioMed Central
Open Access
Research article
Expression of mammalian GPCRs in C. elegans generates novel behavioural responses to human ligands Michelle S Teng1, Martijn PJ Dekkers2, Bee Ling Ng1, Suzanne Rademakers1, Gert Jansen2, Andrew G Fraser1 and John McCafferty*1 Address: 1Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK and 2MGC Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands Email: Michelle S Teng - [email protected]; Martijn PJ Dekkers - [email protected]; Bee Ling Ng - [email protected]; Suzanne Rademakers - [email protected]; Gert Jansen - [email protected]; Andrew G Fraser - [email protected]; John McCafferty* - [email protected] * Corresponding author
Published: 20 July 2006 BMC Biology 2006, 4:22
doi:10.1186/1741-7007-4-22
Received: 06 April 2006 Accepted: 20 July 2006
This article is available from: http://www.biomedcentral.com/1741-7007/4/22 © 2006 Teng et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract Background: G-protein-coupled receptors (GPCRs) play a crucial role in many biological processes and represent a major class of drug targets. However, purification of GPCRs for biochemical study is difficult and current methods of studying receptor-ligand interactions involve in vitro systems. Caenorhabditis elegans is a soil-dwelling, bacteria-feeding nematode that uses GPCRs expressed in chemosensory neurons to detect bacteria and environmental compounds, making this an ideal system for studying in vivo GPCR-ligand interactions. We sought to test this by functionally expressing two medically important mammalian GPCRs, somatostatin receptor 2 (Sstr2) and chemokine receptor 5 (CCR5) in the gustatory neurons of C. elegans. Results: Expression of Sstr2 and CCR5 in gustatory neurons allow C. elegans to specifically detect and respond to somatostatin and MIP-1α respectively in a robust avoidance assay. We demonstrate that mammalian heterologous GPCRs can signal via different endogenous Gα subunits in C. elegans, depending on which cells it is expressed in. Furthermore, pre-exposure of GPCR transgenic animals to its ligand leads to receptor desensitisation and behavioural adaptation to subsequent ligand exposure, providing further evidence of integration of the mammalian GPCRs into the C. elegans sensory signalling machinery. In structure-function studies using a panel of somatostatin-14 analogues, we identified key residues involved in the interaction of somatostatin-14 with Sstr2. Conclusion: Our results illustrate a remarkable evolutionary plasticity in interactions between mammalian GPCRs and C. elegans signalling machinery, spanning 800 million years of evolution. This in vivo system, which imparts novel avoidance behaviour on C. elegans, thus
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