Class C G protein-coupled receptors: reviving old couples with new partners

Thor C Møller,Jean-Philippe Pin,David Moreno-Delgado,Julie Kniazeff

doi:10.1007/s41048-017-0036-9

Abstract

G protein-coupled receptors (GPCRs) are key players in cell communication and are encoded by the largest family in our genome. As such, GPCRs represent the main targets in drug development programs. Sequence analysis revealed several classes of GPCRs: the class A rhodopsin-like receptors represent the majority, the class B includes the secretin-like and adhesion GPCRs, the class F includes the frizzled receptors, and the class C includes receptors for the main neurotransmitters, glutamate and GABA, and those for sweet and umami taste and calcium receptors. Class C receptors are far more complex than other GPCRs, being mandatory dimers, with each subunit being composed of several domains. In this review, we summarize our actual knowledge regarding the activation mechanism and subunit organization of class C GPCRs, and how this brings information for many other GPCRs.

Highlights

CLASS C GPCRS AND TOPOLOGYThe class C of G protein-coupled receptors (GPCRs) contains 22 members, including the eight metabotropic glutamate receptors, the GABAB receptors (GABAB1 and GABAB2), the calcium-sensing receptor (CaS) and the taste receptors (T1R1–T1R3) (Fredriksson et al 2003)
The mGlu receptors have been further classified into three different groups depending on their similarities in sequence, pharmacology, signalling and localization: Group I includes mGlu1 and mGlu5, Group II mGlu2 and mGlu3 and Group III mGlu4, mGlu6, mGlu7 and mGlu8
The Venus flytrap (VFT) domain is connected to the seven-transmembrane

Summary

INTRODUCTION

The class C of G protein-coupled receptors (GPCRs) contains 22 members, including the eight metabotropic glutamate receptors (mGlu1–8), the GABAB receptors (GABAB1 and GABAB2), the calcium-sensing receptor (CaS) and the taste receptors (T1R1–T1R3) (Fredriksson et al 2003). Agonists bind to the VFT domain of one protomer and promote active conformation of the 7TM domain of the other protomer (Galvez et al 2001; Margeta-Mitrovic et al 2001b), implying that trans-activation is the main process for G protein activation in these heterodimers (Fig. 2) Compared to homodimers, this results from a slightly different mechanism. Cooperativity between protomers exists in class C GPCR heterodimers It has been shown in the GABAB receptor that the GABAB2 VFT and the GABAB1 7TM domains are not directly involved in ligand binding and G protein activation, they play a key role in defining the activation potency. Abbreviations 7TM domain CaS receptor CRD GABA GPCR mGlu receptor NAM PAM TM VFT

Compliance with ethical standards

Findings

CONCLUSIONS