Asymmetry is central to excitatory glutamate receptor activation

Excitatory neurotransmission by glutamate is modulated by eight dimeric transmembrane-spanning metabotropic glutamate receptors (mGlu) in mammals. These receptors influence neuronal excitability, neurotransmitter release and synaptic plasticity and are promising therapeutic targets for psychiatric and neurological disorders. Three studies published in Nature report the first full-length structures for three mGlu receptor subtypes. Lin et al.1 used cryo-EM to obtain structures of homodimeric metabotropic glutamate receptor subtype 2 (mGlu2) and subtype 4 (mGlu4), both in complex with heterotrimeric Gi protein. Complementary work from the same team provides structural insights into inactive mGlu2 and mGlu7 homodimers, an inactive heterodimer containing mGlu2 and mGlu7, and an agonist-bound mGlu2 homodimer transition state2. In parallel, Seven et al.3 report multiple cryo-EM structures of mGlu2 homodimers, including in inactive and transitional states and in the active state in complex with heterotrimeric Gi protein. A wide spectrum of conformational changes within these multidomain dimeric receptors is captured, revealing insights into how the binding of agonists and small molecules gives rise to asymmetric active complexes with heterotrimeric G proteins, which are required to trigger intracellular signaling.