Résumé
The most abundant excitatory neurotransmitter of the brain, glutamate, activates two sets of receptors: the ionotropic glutamate receptors responsible for the fast synaptic transmission and the metabotropic glutamate receptors (mGluRs) which regulate synaptic transmission. Thus, mGluRs are involved in fundamental physiological processes such as learning and memory, cardiac and movement control or pain. However, they also contribute to some neurological diseases. These receptors are then considered as good therapeutic targets. They share less than 10% sequence identity with the rhodopsin-related or the glucagon receptor-related receptors. Moreover, in addition to a heptahelical domain (HD) responsible for the coupling to G proteins, they possess a large extracellular domain containing the ligand binding site. Until recently, the functioning of these receptors was poorly understood. We have shown that several mGluRs displayed a constitutive activity, which was controlled by their C-terminal tail, and could be involved in long-term regulation of neuronal processes. Moreover, we showed that only noncompetitive allosteric compounds acting directly in the heptahelical domain were able to block this constitutive activity. These compounds allowed a better understanding of the mGluR activation process. Together with the recent determination of the crystal dimeric structure of the extracellular glutamate binding domain (BD) of mGluR1, our results led to a theoretical model for the functioning of this receptor.