Heterodimers Revolutionize the Field of Metabotropic Glutamate Receptors

Identified 40 years ago, the metabotropic glutamate (mGlu) receptors play key roles in modulating many synapses in the brain, and are still considered as important drug targets to treat various brain diseases. Eight genes encoding mGlu subunits have been identified. They code for complex receptors composed of a large extracellular domain where glutamate binds, connected to a G protein activating membrane domain. They are covalently linked dimers, a quaternary structure needed for their activation by glutamate. For many years they have only been considered as homodimers, then limiting the number of mGlu receptors to 8 subtypes composed of twice the same subunit. Twelve years ago, mGlu subunits were shown to also form heterodimers with specific subunits combinations, increasing the family up to 19 different potential dimeric receptors. Since then, a number of studies brought evidence for the existence of such heterodimers in the brain, through various approaches. Structural and molecular dynamic studies helped understand their peculiar activation process. The present review summarizes the approaches used to study their activation process and their pharmacological properties and to demonstrate their existence in vivo. We will highlight how the existence of mGlu heterodimers revolutionizes the mGlu receptor field, opening new possibilities for therapeutic intervention for brain diseases. As illustrated by the number of possible mGlu heterodimers, this study will highlight the need for further research to fully understand their role in physiological and pathological conditions, and to develop more specific therapeutic tools.