Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2016) 41 S20.3 | DOI: 10.1530/endoabs.41.S20.3

ECE2016 Symposia Hitchhiker's guide to the microsmos of GPCRs (3 abstracts)

Innovative approaches for the control of class C GPCRs activity

Jean-Phillippe Pin


France.


G protein-coupled receptors play key roles in cell-cell communication processes, and, not surprisingly, are the main targets for therapeutic drugs. Among these, those of the class C are the receptors for neurotransmitters, glutamate and GABA (mGlu and GABABRs), for the umami and sweet taste compounds (T1Rs), and for calcium and basic amino acids (CaSR and GPRC6a). Class C GPCRs are much more complex proteins than the class A and B GPCRs. They are made of two subunits covalently linked by a disulfide bridge, each being composed of a venus flytrap domain (VFT) where agonists bind, connected via a cystein-rich domain to a heptahelical membrane domain responsible for G protein activation. Such a large protein complex undergoes major conformational changes upon ligand binding in the VFT, leading to the activation of one 7TM domain.

During this presentation, I will summarize our view of the activation mechanism of these receptors, and illustrate the multiple possibilities offered to develop innovative molecules able to specifically regulate them. These include orthosteric as well as allosteric compounds acting within the 7TM. Recently, photo-switchable compounds have been developed that allow to control receptor activity where and when needed. Using such compounds identified for mGluRs, we demonstrated that it is possible to perfectly control the response to pain in living animals.

The important conformational changes accompanying class C receptor activation offers the possibilities to develop antibodies that can regulate their activity. We identified llama single chain antibodies (nanobodies) that act as positive allosteric modulators of mGlu2 subtype. These nanobodies control mGlu2 activity in brain slices, enhancing the presynaptic inhibitory effect of mGlu2 agonists. In addition, injection of these nanobodies in the hippocampal area enhance to inhibitory action of mGlu2 agonists of the context fear memory.

These findings illustrate the numerous possibilities offered by the class C GPCR complex structure to modulate their activity.

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