**Part 1**

**Pharmacodynamic** 

**1** 

*France* 

**Metabotropic Receptors** 

**for Glutamate and GABA** 

*Institut de Génomique Fonctionnelle,* 

Gregory Stewart, Julie Kniazeff, Laurent Prézeau, Philippe Rondard, Jean-Philippe Pin and Cyril Goudet

*CNRS UMR5203 - INSERM U661 - Universités Montpellier 1&2* 

G protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and due to their ubiquitous expression and vast array of functions they present attractive targets for the treatment of a wide number of diseases and disorders. Accordingly, they represent up to 30% of targets of current therapeutics (Overington et al., 2006). Despite the capacity of GPCRs to modulate many (patho-)physiological functions there is a high attrition rate with regard to new compounds entering clinical trials. There are many reasons for the number of failed drug-like compounds such as non-specificity, unfavourable pharmacokinetic profile and lack of clinical efficacy. In this regard, molecules targeting neurotransmitter receptors in the CNS traditionally have poor side-effect profiles due to the high concentrations required to pass the blood-brain barrier. There remain many specific challenges in drug discovery such as promiscuous GPCR-effector coupling; differential celland tissue-specific effects; ligand-induced changes in receptor trafficking; and proteinprotein interactions and receptor oligomerisation (Galandrin et al., 2007; Hanyaloglu and

von Zastrow, 2008; Kniazeff et al., 2011; Wettschureck and Offermanns, 2005).

GPCRs are divided into three main classes (A-C) based on structural homology; however all GPCRs possess a 7-alpha-helical transmembrane-spanning (7TM) domain, which facilitates the transduction of extracellular signals into intracellular responses. GPCRs recognise a myriad of different stimuli from photons, amino acids and biogenic amines to large peptides and proteins. Class A (rhodopsin-like) GPCRs are among the best characterised and consist of a relatively short N-terminal domain, a 7TM domain connected by extracellular and intracellular loops, and an intracellular C-terminal domain (Fredriksson et al., 2003). Class B (secretin-like) GPCRs have comparatively long N-terminal domains with similar 7TM and C-terminal topography as Class A receptors. By far and away, Class C (glutamate-like) GPCRs have the most distinct topography compared the other GPCRs; they possess large, structured N-terminal domains, which form a venus-fly trap-like structure known as the venus-fly trap (VFT) domain. The VFT domain is often (with exceptions) connected to the 7TM domain via a cysteine-rich domain, and further to this the C-terminal domain is often comparatively longer than those of Class A GPCRs. Structurally, all GPCRs are similar in their 7TM domains, yet the activation mechanisms, at least by the endogenous ligand varies

**1. Introduction** 
